Papers - Kinouchi, Kenichiro

特集 総排泄腔遺残症 総排泄腔遺残症の術後遠隔期における問題とDSDセンターの意義

加藤 源俊, 佐藤 壮泰, 熊谷 知子, 杉山 祥基, 城崎 浩司, 山岸 徳子, 工藤 裕実, 鈴木 悠史, 佐藤 温子, 市橋 洋輔, 狩野 元宏, 木内 謙一郎, 木須 伊織, 内田 明花, 山田 洋平, 佐々木 掌子, 菊地 俊暁, 鳴海 覚志, 浅沼 宏, 藤野 明浩

小児外科 (東京医学社)  57 ( 11 ) 1179 - 1182 2025.11

Lead author, Last author, Corresponding author,  ISSN  03856313

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Effects of perirenal fat accumulation on cardiometabolic and renal functions and mineralocorticoid receptor activation in primary aldosteronism.

Ryunosuke Mitsuno, Toshifumi Nakamura, Kengo Nakamura, Kenji Kaneko, Daiki Kojima, Yosuke Mizutani, Yoshitake Yamada, Masahiro Jinzaki, Tatsuhiko Azegami, Takeshi Kanda, Kenichiro Kinouchi, Hiroshi Itoh, Jun Yoshino, Kaori Hayashi

Hypertension research : official journal of the Japanese Society of Hypertension 48 ( 12 ) 3244 - 3256 2025.10

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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Perirenal fat (PRF), an ectopic fat depot lying adjacent to kidneys, is a risk factor for cardiometabolic and renal dysfunctions in patients with obesity and type 2 diabetes. We aimed to investigate the involvement of PRF in the pathophysiology and treatment of primary aldosteronism (PA). To this end, we measured PRF volume by abdominal CT and evaluated the relationships among PRF volume, cardiometabolic and renin-angiotensin-aldosterone system (RAAS) parameters, and therapeutic response to mineralocorticoid receptor antagonist (MRA) treatment in well-phenotyped PA patients. In addition, we evaluated the effects of MRA treatment on inflammation and fibrosis, potential downstream targets of MR signaling, by analyzing PRF obtained from obese (db/db) mice. PRF volume (PRF%) and visceral fat volume (VFV) were associated with various cardiometabolic and renal risk markers and RAAS parameters, such as body mass index, creatinine, triglyceride, high-density lipoprotein cholesterol, uric acid, fasting glucose, C-reactive protein, 24-h urine aldosterone, and 24-h urine normetanephrine (all P < 0.05). PRF%, but not VFV, positively correlated with changes in systolic and diastolic blood pressure and initial estimated glomerular filtration rate (eGFR) fall following MRA treatment after adjusting for confounders (all P < 0.05). In addition, MRA treatment decreased PRF expression of markers of macrophage infiltration and fibrosis in db/db mice (all P < 0.05). In conclusion, our results suggest that PRF accumulation is involved in the mechanisms linking MR activation to cardiometabolic and renal dysfunctions in PA patients. Moreover, PRF could be not only a prognostic factor but also a new therapeutic target for MRA-resistant hypertension.

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Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry.

Aika Hagiwara, Shintaro Yamaguchi, Kazutoshi Miyashita, Kenichiro Kinouchi, Kaori Hayashi, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 48 ( 10 ) 2664 - 2676 2025.10

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote weight loss in patients with type 2 diabetes mellitus; however, the underlying mechanisms remain unknown. This study investigated the role of renal autonomic nerves in SGLT2 inhibitor-induced lipolysis and body weight reduction by utilizing the renal denervation technique. The results indicated that renal autonomic nerves mediated lipolysis in mice fed a high-fat diet following treatment with tofogliflozin, an SGLT2 inhibitor. The effect was attenuated by renal denervation or β3-adrenergic blockade. Metabolomic analysis revealed that treatment with tofogliflozin elevated renal adenosine, which in turn activated adipose sympathetic nerves, as evidenced by increased norepinephrine concentrations in adipose tissue, thereby promoting lipolysis. These findings uncover a novel reno-adipose neurocircuitry linking renal energy depletion to systemic fatty acid oxidation, providing insights into the sustained weight-reducing effects of SGLT2 inhibitors. A scheme illustrating SGLT2 inhibitor-induced activation of reno-adipose autonomic neurocircuitry, which promotes lipolysis and weight reduction.

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Vascular Endothelial NAMPT-Mediated NAD+ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice.

Shotaro Kosugi, Shintaro Yamaguchi, Ken Nishioka, Taichi Nagahisa, Yasuhiro Watanabe, Daiki Kojima, Kenji Kaneko, Ryunosuke Mitsuno, Ran Nakamichi, Yoshinaga Kawano, Kenichiro Kinouchi, Koichiro Homma, Takeshi Kanda, Junichiro Irie, Kazutoshi Miyashita, Toshiaki Monkawa, Jun Yoshino, Hiroshi Itoh, Kaori Hayashi

Aging cell 24 ( 11 ) e70222 2025.09

Lead author, Last author, Corresponding author, Accepted,  ISSN  1474-9718

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Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD+) biosynthesis correlates with aging and aging-associated complications. However, the precise molecular mechanisms linking aging-associated NAD+ deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, influences vascular endothelial function and whole-body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell-specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high-fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD+-dependent deacetylase sirtuin-1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD+ depletion driven by an imbalance between NAMPT-mediated NAD+ biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD+ levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging-associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT-NAD+-SIRT1-eNOS signaling related to aging-associated cardiometabolic disorders.

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A systematic review to compare adrenalectomy and mineralocorticoid receptor antagonists in patients with unilateral primary aldosteronism.

Yuichi Yoshida, Kenichiro Kinouchi, Satoshi Nagai, Atsushi Sakima, Yoichi Takami, Hisatomi Arima, Kazutoshi Miyashita, Masashi Mukoyama

Hypertension research : official journal of the Japanese Society of Hypertension 48 ( 9 ) 2368 - 2375 2025.09

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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To date, no systematic review has examined whether adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment is more effective in patients with unilateral primary aldosteronism (uPA). Comparing clinical and biochemical data before and after treatment, we performed a systematic review to determine whether either ADX or MRA treatment is superior to the other in patients with uPA. Article search was performed using the PubMed, Cochrane Library, and ICHUSHI electronic databases. A comparative analysis was performed when at least 3 articles were available in each outcome. The collected data were used to calculate the effect measures represented as mean difference (MD) or odds ratio (OR). Our search strategy identified 526 abstracts, of which 7 research papers were finally included in the analysis. ADX for uPA patients significantly reduced the incidence of cerebro-cardiovascular disease (OR 0.63 [95% confidence interval 0.46, 0.85]), lowered the systolic BP (-8.78 mmHg [-11.61, -5.95]), and increased the serum potassium levels (0.43 mmol/L [0.35, 0.51]) compared to MRAs. In conclusion, ADX is more effective than MRA treatment in patients with uPA, but with higher risk of increased serum potassium levels. Graphical abstract: ADX adrenalectomy, MRAs mineralocorticoid receptor antagonists, PA primary aldosteronism, SBP systolic blood pressure.

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131I-MIBG治療により遅発的に血糖値改善が得られた糖尿病合併褐色細胞腫の1例

中村 俊文, 川野 義長, 水谷 洋佑, 木内 謙一郎, 林 香

日本内科学会関東地方会 (日本内科学会-関東地方会)  705回   np27 - np27 2025.06

Lead author, Last author, Corresponding author

甲状腺癌術前CT検査で偶発的に発見された巨大下垂体腫瘍を伴う先端巨大症の一例

小宮山 紘史, 中村 俊文, 水谷 洋佑, 木内 謙一郎, 植田 良, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  101 ( 1 ) 390 - 390 2025.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

下垂体卒中を合併した先端巨大症の一例

神戸 理紗, 水谷 洋佑, 中村 俊文, 木内 謙一郎, 植田 良, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  101 ( 1 ) 368 - 368 2025.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

副腎静脈サンプリングおよびアドステロールシンチグラフィにより治療方針を検討したPPNADの1例

吉岡 桜子, 中村 俊文, 水谷 洋佑, 木内 謙一郎, 田村 全, 中塚 誠之, 武田 利和, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  101 ( 1 ) 308 - 308 2025.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

右側腹部痛を契機に診断された、ACTH抑制がみられなかったCushing症候群を伴う副腎癌の1例

田倉 裕介, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 武田 利和, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  101 ( 1 ) 388 - 388 2025.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

Endocrinology in maternal-fetal synchronization and developmental origins of susceptibility to metabolic diseases

Kenichiro Kinouchi, Hiroshi Itoh

Endocrine Journal  2025

Lead author, Last author, Corresponding author, Accepted,  ISSN  0918-8959

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On the imperative of including 24-h and longitudinal multidimensional physiological phenotyping in rodent models of sleep apnea

Gaucher, J., Vial, G., Bouyon, S., Brian?on-Marjollet, A., Faury, G., Arnaud, C., Bailly, S., Tamisier, R., Kinouchi, K., Baldi, P., Gozal, D., P{\'e}pin, J.-L.

Sleep Medicine 127   133 - 137 2025

Lead author, Last author, Corresponding author,  ISSN  1878-5506

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造影CT検査では同定困難であったインスリノーマの1例

大曽根 史織, 木内 謙一郎, 浅井 愛未, 水谷 洋佑, 中村 俊文, 田村 全, 中塚 誠之, 北郷 実, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 2 ) 626 - 626 2024.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

ACTH依存性にテストステロン産生を来した副腎機能低下症の一例

浅井 愛未, 中村 俊文, 水谷 洋佑, 木内 謙一郎, 小林 佐紀子, 石井 智弘, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 2 ) 604 - 604 2024.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

低Ca血症の精査で診断に至った偽性副甲状腺機能低下症の1例

三角 昂之, 木内 謙一郎, 水谷 洋佑, 中村 俊文, 石井 智弘, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 2 ) 620 - 620 2024.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

COVID-19に両側副腎出血を続発した抗リン脂質抗体症候群の1例

豊浦 文, 中村 俊文, 水谷 洋佑, 木内 謙一郎, 林 侑太朗, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 2 ) 645 - 645 2024.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

原発性アルドステロン症における腎周囲脂肪蓄積の臨床的意義

満野 竜ノ介, 中村 俊文, 金子 賢司, 児島 大輝, 中村 健吾, 水谷 洋佑, 山田 祥岳, 畔上 達彦, 神田 武志, 木内 謙一郎, 吉野 純, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 2 ) 642 - 642 2024.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

造影剤アレルギーのため炭酸ガス造影とcone beam CTで副腎静脈サンプリングを行った原発性アルドステロン症の一例

吉岡 桜子, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 小林 佐紀子, 乃村 元子, 中塚 誠之, 田村 全, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 392 - 392 2024.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

オシロドロスタット投与により病勢のコントロールが得られたクッシング病の一例

増田 佳奈子, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 小林 佐紀子, 乃村 元子, 伊藤 裕, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 370 - 370 2024.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

保険収載後に施行したラジオ波焼灼術で奏功が確認されたアルドステロン産生腺腫の1例

三角 昂之, 中村 俊文, 水谷 洋佑, 木内 謙一郎, 小林 佐紀子, 中塚 誠之, 田村 全, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  100 ( 1 ) 424 - 424 2024.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

増刊号特集 薬の使い方がすぐわかる　泌尿器科処方ガイド 6.内分泌疾患 原発性アルドステロン症

木内 謙一郎

臨床泌尿器科 (株式会社医学書院)  78 ( 4 ) 110 - 113 2024.04

Lead author, Last author, Corresponding author,  ISSN  03852393

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【薬の使い方がすぐわかる　泌尿器科処方ガイド】内分泌疾患　原発性アルドステロン症

木内 謙一郎

臨床泌尿器科 ((株)医学書院)  78 ( 4 ) 110 - 113 2024.04

Lead author, Last author, Corresponding author,  ISSN  0385-2393

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＜文献概要＞処方のポイント　●原発性アルドステロン症のスクリーニングや確定診断のための検査の際には,可能な限りレニン・アンジオテンシン系に影響がない薬剤を選択する.また,低カリウム血症を合併する症例では,カリウム製剤による血清カリウム値の補正を十分に行ったうえで検査を実施する.●原発性アルドステロン症の確定診断に至った高血圧の症例では,禁忌がない限りミネラルコルチコイド受容体拮抗薬(MRB)を第一選択とする.

【糖尿病-その病態と,予後決定因子,治療薬が教えてくれること】糖質制限・時間制限食のエビデンスと可能性

山田 悟, 木内 謙一郎

カレントテラピー ((株)ライフメディコム)  42 ( 2 ) 150 - 154 2024.02

Lead author, Last author, Corresponding author,  ISSN  0287-8445

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インスリン発見以前,糖質制限食は唯一の糖尿病治療法であった.インスリン療法の普及とともに20世紀では民間療法として扱われていたが,21世紀になり,血糖改善に最善の食事法とされるに至っている.1型糖尿病,2型糖尿病を問わず,HbA1c改善や低血糖頻度減少や薬剤費軽減を期待可能な食事法であり,わが国でのさらなる普及が期待されている.一方で,時間制限食は概日時計や栄養センシング分子の活性化を介して,体重減少や耐糖能改善,血圧低下などの心血管内分泌代謝の改善効果が示されており,糖尿病,高血圧,メタボリック症候群などの生活習慣病に対する新たな食事法として注目されている.本稿では,糖質制限や時間制限食のエビデンスと可能性を概説する.(著者抄録)

Diurnal variation in the association between the scan frequency of isCGM and CGM metrics: post hoc analysis of the ISCHIA study

Meguro, S., Sakane, N., Hosoda, K., Hirota, Y., Itoh, A., Kato, K., Kodani, N., Kuroda, A., Matsuhisa, M., Miura, J., Shimada, A., Tone, A., Toyoda, M., Murata, T., Fukunaga, M., Kouyama, K., Tanaka, T., Tenta, M., Matsushita, Y., Takeda, M., Iseda, I., Hida, K., Nagao, T., Taniguchi, R., Tanaka, N., Abe, K., Hitaka, Y., Matoba, Y., Katsuno, T., Kusunoki, Y., Fukuda, T., Shimizu, I., Tsuchiya, T., Yagi, K., Sugiyama, K., Yamaguchi, S., Kinouchi, K., Inaishi, J., Nakajima, Y., Mitsuishi, M., Tanaka, M., Irie, J., Saisho, Y., Itoh, H., Kawashima, S., Haisa, A., Satomura, A., Oikawa, Y., Saito, N., Kimura, M., Tsuchida, Y., Shimura, K., Hoshina, S., Takagi, S., Kobayashi, H., Shen, Z., Suganuma, A., Watanabe, T., Ito, Y., Suzuki, S., Kasama, S., Kasahara, M., Kouyama, R., Satoh-Asahara, N., Miyamoto, Y., Nishimura, K.

Diabetology International 15 ( 4 ) 828 - 836 2024

Lead author, Last author, Corresponding author,  ISSN  2190-1686

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Background and aims: To investigate the association between the frequency of intermittent-scanning continuous glucose monitoring (isCGM) and diurnal variation of time in range (TIR), time above range (TAR), and time below range (TBR), we performed a post hoc analysis of the ISCHIA study, a multicenter, prospective, open-label, randomized crossover study of patients with type 1 diabetes mellitus. Method: Data of 93 people who completed the ISCHIA study were used. We calculated scan frequency, TAR, TIR, and TBR of four approximately 6-h intervals: 6:00–11:59 (morning), 12:00–17:59 (afternoon), 18:00–23:59 (evening), and 0:00–5:59 (night). The correlation between scan frequency and diurnal variation of CGM metrics was analyzed using nonparametric Spearman correlation analysis. Results: More frequent scanning was associated with higher TIR in the afternoon (rho = 0.343, P < 0.001), evening (rho = 0.243, P = 0.019), and night (rho = 0.218, P = 0.036); furthermore, it was associated with lower TAR in the afternoon (rho = -0.275, P = 0.008) and TBR in the evening (rho = -0.235, P = 0.024). Concern about the effect of blood glucose fluctuation on social communication affected the number of scans during the day. Concerns about loneliness and hypoglycemia when alone also influenced the number of nighttime scans. Conclusion: Scan frequency is influenced by psychological factors. Afternoon scans were associated with the highest increase in TIR and decrease in TAR. Evening scans were linked to a reduction in TBR.

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Predictors of the effectiveness of isCGM usage in adults with type 1 diabetes mellitus: post-hoc analysis of the ISCHIA study

Fukunaga, M., Kouyama, K., Tanaka, T., Tenta, M., Matsushita, Y., Takeda, M., Iseda, I., Hida, K., Nagao, T., Taniguchi, R., Tanaka, N., Abe, K., Hitaka, Y., Matoba, Y., Katsuno, T., Kusunoki, Y., Fukuda, T., Shimizu, I., Kodani, N., Tsuchiya, T., Yagi, K., Sugiyama, K., Itoh, A., Yamaguchi, S., Kinouchi, K., Inaishi, J., Nakajima, Y., Mitsuishi, M., Tanaka, M., Irie, J., Saisho, Y., Itoh, H., Meguro, S., Kawashima, S., Haisa, A., Satomura, A., Oikawa, Y., Shimada, A., Saito, N., Kimura, M., Tsuchida, Y., Shimura, K., Hoshina, S., Takagi, S., Kobayashi, H., Shen, Z., Suganuma, A., Watanabe, T., Ito, Y., Suzuki, S., Kasama, S., Kasahara, M., Tone, A., Miura, J., Kouyama, R., Kato, K., Kuroda, A., Matsuhisa, M., Hirota, Y., Toyoda, M., Satoh-Asahara, N., Sakane, N., Murata, T., Miyamoto, Y., Nishimura, K., Hosoda, K., Murata, T.

Diabetology International 15 ( 3 ) 400 - 405 2024

Lead author, Last author, Corresponding author,  ISSN  2190-1686

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Aim: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). Participants and methods: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. Results: Pearson’s correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = − 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = − 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). Conclusions: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.

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Predicting the laterality of the autonomous aldosterone production from adrenal vein sampling

Kinouchi, K., Hayashi, K.

Hypertension Research (Springer Science and Business Media LLC)  47 ( 2 ) 543 - 544 2024

Lead author, Last author, Corresponding author,  ISSN  1348-4214

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Association Between Renal Sinus Fat and Cardiometabolic and Renin-Angiotensin System Parameters in Primary Aldosteronism.

Ryunosuke Mitsuno, Kenji Kaneko, Toshifumi Nakamura, Daiki Kojima, Yosuke Mizutani, Tatsuhiko Azegami, Shintaro Yamaguchi, Yoshitake Yamada, Masahiro Jinzaki, Kenichiro Kinouchi, Jun Yoshino, Kaori Hayashi

Journal of the Endocrine Society (The Endocrine Society)  8 ( 1 ) bvad154 2023.12

Lead author, Last author, Corresponding author,  ISSN  24721972

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CONTEXT: Renal sinus fat (RSF) accumulation is associated with cardiometabolic diseases, such as obesity, diabetes, hypertension, and chronic kidney disease. However, clinical implications of RSF in primary aldosteronism (PA) remain unclear. OBJECTIVE: We aimed to investigate relationships between RSF volume and key cardiometabolic and renin-angiotensin system (RAS) parameters in PA patients and clarify the differences in these relationships between unilateral and bilateral subtypes. METHODS: We analyzed data obtained from well-characterized PA patients that involved 45 unilateral (median age: 52 years; 42.2% men) and 92 bilateral patients (51 years; 42.4% men). RESULTS: RSF volume normalized by renal volume (RSF%) was greater in the unilateral group than in the bilateral group (P < .05). RSF% was greater in men than in women (P < .05). RSF% positively correlated with parameters related to cardiometabolic risk, including age, body mass index, visceral fat volume, creatinine, triglycerides/high-density lipoprotein cholesterol ratio, uric acid, fasting glucose, and C-reactive protein regardless of PA subtypes (all P < .05). Intriguingly, RSF% positively correlated with plasma aldosterone concentration (PAC), aldosterone-to-renin ratio, and intact parathyroid hormone (iPTH) (all P < .05) in bilateral patients but did not correlate with RAS parameters and even showed an opposite trend in unilateral patients. In subgroup analyses by sex, these distinctions became more evident in women. After adjustment for potential confounders, RSF% remained positively correlated with PAC and iPTH in bilateral patients. CONCLUSION: Our results indicate that RSF accumulation is involved in cardiometabolic dysfunction associated with PA. However, there were distinct correlations between RSF volume and RAS parameters according to sex and PA subtypes.

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内分泌障害を伴ったPOEMS症候群の一例

増田 佳奈子, 小林 佐紀子, 木内 謙一郎, 中村 俊文, 藤井 高幸, 清水 隆之, 伊藤 裕, 林 香

日本内分泌学会雑誌 ((一社)日本内分泌学会)  99 ( 2 ) 614 - 614 2023.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

Adipocyte NMNAT1 expression is essential for nuclear NAD+ biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism.

Shintaro Yamaguchi, Daiki Kojima, Tooba Iqbal, Shotaro Kosugi, Michael P Franczyk, Nathan Qi, Yo Sasaki, Keisuke Yaku, Kenji Kaneko, Kenichiro Kinouchi, Hiroshi Itoh, Kaori Hayashi, Takashi Nakagawa, Jun Yoshino

Biochemical and biophysical research communications (Elsevier BV)  674   162 - 169 2023.09

Lead author, Last author, Corresponding author,  ISSN  0006-291X

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Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.

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1型糖尿病モデルマウスにおける腎臓の代謝変容から見た腎障害進展機序の解明

押田 卓磨, 宮下 和季, 久保 亜紀子, 中村 俊文, 木内 謙一郎, 伊藤 裕, 林 香

日本高血圧学会総会プログラム・抄録集 ((NPO)日本高血圧学会)  45回   371 - 371 2023.09

Lead author, Last author, Corresponding author

Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation.

Sho Endo, Asuka Uto, Kazutoshi Miyashita, Masaaki Sato, Hiroyuki Inoue, Kentaro Fujii, Aika Hagiwara, Masaki Ryuzaki, Takuma Oshida, Kenichiro Kinouchi, Hiroshi Itoh

Journal of the Endocrine Society (The Endocrine Society)  7 ( 7 ) bvad082 2023.06

Lead author, Last author, Corresponding author,  ISSN  24721972

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To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF.

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The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming.

Shogo Sato, Tomoaki Hishida, Kenichiro Kinouchi, Fumiaki Hatanaka, Yumei Li, Quy Nguyen, Yumay Chen, Ping H Wang, Kai Kessenbrock, Wei Li, Juan Carlos Izpisua Belmonte, Paolo Sassone-Corsi

Cell reports (Elsevier BV)  42 ( 6 ) 112590 - 112590 2023.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  22111247

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Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.

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術前画像診断に苦慮した脂肪・骨髄化生を伴うコルチゾール産生腺腫の一例

浅井 愛未, 小林 佐紀子, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 宮下 和季, 澤原 夢, 乃村 元子, 武田 利和, 上野 彰久, 新井 恵吏, 真杉 洋平, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  99 ( 1 ) 393 - 393 2023.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

Cushing症候群精査中に妊娠が判明し妊娠17週で副腎切除術を行った症例

水谷 洋佑, 小林 佐紀子, 木内 謙一郎, 中村 俊文, 丸木 友美, 乃村 元子, 武田 利和, 玉井 順子, 池ノ上 学, 田中 守

日本内分泌学会雑誌 ((一社)日本内分泌学会)  99 ( 1 ) 394 - 394 2023.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

体内時計の同調による代謝恒常性と肥満

岩原 彰秀, 加藤 恭介, 木内 謙一郎, 伊藤 裕

Precision medicine = プレシジョンメディシン / 「Precision medicine」編集委員会 編 (東京 : 北隆館)  6 ( 5 ) 346 - 349 2023.05

Lead author, Last author, Corresponding author,  ISSN  24343625

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クッシング症候群を併発した男性ホルモン産生副腎腫瘍の一例

遊木 一成, 小林 佐紀子, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 宮下 和季, 増田 佳奈子, 乃村 元子, 武田 利和, 上野 彰久, 新井 恵吏, 大喜多 肇, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  99 ( 1 ) 394 - 394 2023.05

Lead author, Last author, Corresponding author,  ISSN  0029-0661

【体内時計のprecision medicine】体内時計の同調による代謝恒常性と肥満

岩原 彰秀, 加藤 恭介, 木内 謙一郎, 伊藤 裕

Precision Medicine ((株)北隆館)  6 ( 5 ) 346 - 349 2023.05

Lead author, Last author, Corresponding author,  ISSN  2434-3625

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昼夜の明暗周期に同期しながらも,自律的で固有の約24時間周期のリズムを生体は有しており,概日リズムと呼ばれる。概日リズムは生体時計を中心とする転写翻訳フィードバック機構を基軸に,代謝恒常性を維持している。近年の研究から,夜勤や深夜の食事が概日リズムの乱れを通じて,肥満の原因となることが明らかになってきた。これまで肥満に関わる知見の多くが,カロリー摂取量やエネルギー消費量に焦点が当てられてきたが,食事摂取や空腹のタイミングが重要な役割を果たすことが分かってきている。本項では,概日リズムの同調因子としての食事のタイミングと内分泌代謝リズムの肥満の病態への関与を概説する。(著者抄録)

テストステロン産生副腎腫瘍から二次性多血症を発症した1例

新藤 隆英, 松木 絵里, 木内 謙一郎, 片岡 圭亮

臨床血液 ((一社)日本血液学会-東京事務局)  64 ( 4 ) 301 - 301 2023.04

Lead author, Last author, Corresponding author,  ISSN  0485-1439

PS-B07-4: ADMINISTRATION OF AMINO ACIDS PROVOKES EXPRESSION OF PRO-FIBROTIC GENES IN MURINE CULTURED FIBROBLAST CELLS

Takuma Oshida, Kazutoshi Miyashita, Akiko Kubo, Masaaki Sato, Kentaro Fujii, Masaki Ryuzaki, Asuka Uto, Toshifumi Nakamura, Kenichiro Kinouchi, Sakiko Kobayashi, Hiroshi Ito

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e371 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:sec> <jats:title>Objective:</jats:title> <jats:p>Diabetic kidney disease (DKD) has been the most common cause of end-stage renal disease (ESRD) which leads to hemodialysis for more than 20 years in Japan. Various reports have been published on the mechanisms underlying the progression of DKD, however, many details remain unclear. We investigated the mechanisms underlying the progression of renal fibrosis and kidney injury in hyperglycemia from the viewpoint of metabolic alteration in the kidney by using streptozotocin-treated mice (STZ mice).</jats:p> </jats:sec> <jats:sec> <jats:title>Design/Methods:</jats:title> <jats:p>8 weeks old ICR mice were treated with streptozotocin (200 mg/kg intra-peritoneally), to produce type 1 diabetes mellitus model mice. The kidneys of those mice were collected 4 weeks after STZ treatment and examined for metabolites that were altered in the kidneys of STZ mice by metabolome analysis. Amino acids that were increasing in the kidneys of STZ mice were administered to L929 murine fibroblast cells, and expression of pro-fibrotic genes were examined.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>STZ-treatment caused progression of renal fibrosis in mice under both low- and high-protein diets. Metabolome analysis of the kidneys in STZ mice showed marked alterations of amino acids in the kidneys. Increased levels of branched chain amino acids (BCAAs) such as valine and leucine were observed. Among these amino acids, leucine administration to L929 cells resulted in increased expression of genes promoting renal fibrosis.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Alterations of BCAAs in the kidneys due to hyperglycemia in STZ mice may affect progression of renal fibrosis and kidney injury. We are now investigating the mechanism by which BCAAs contribute to renal fibrosis.</jats:p> </jats:sec>

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PS-R07-5: A CASE OF PRIMARY ALDOSTERONISM WITH DECLINED GLOMERULAR FILTRATION RATE AFTER ADRENALECTOMY

Hikari Kohmoto, Sakiko Kobayashi, Kazutoshi Miyashita, Kenichiro Kinouchi, Toshifumi Nakamura, Yosuke Mizutani, Toshikazu Takeda, Mototsugu Oya, Masashi Tamura, Seishi Nakatsuka, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e511 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>Primary aldosteronism (PA) has been known to cause organ damage, such as renal and cardiovascular disorders more frequently than essential hypertension (EH), independently of blood pressure. Among renal disorders, albuminuria is more prevalent in patients with PA than EH, while GFR tends to be higher in PA due to glomerular hyperfiltration. Surgical and medical treatments for PA correct these effects of excess aldosterone, which sometimes uncover preexisting chronic kidney disease (CKD). Here we present a case of PA with CKD who manifested decline of glomerular filtration rate (GFR) and overt renal failure following resection of aldosterone-producing adenoma.</jats:p> </jats:sec> <jats:sec> <jats:title>Case report:</jats:title> <jats:p>A 53-year-old woman was diagnosed with hypertension at the age of 40. Her primary care physician started treatment with a calcium channel blocker (CCB). At the age of 49, she was diagnosed with Sjogren's syndrome (SS). Blood tests revealed severe hypokalemia and eGFR of 50 mL/min/1.73m2, while 24-hr urine collection showed urinary protein of 0.5 g per day. SS was suspected to underlie her renal disease. A renal biopsy was performed, and suggested nephrosclerosis and IgA nephropathy. On the other hand, a 11mm-sized tumor in the left adrenal gland was discovered during the investigation of secondary hypertension. PA was confirmed based on active renin concentration (ARC) of 4.3 pg/mL, plasma aldosterone concentration (PAC) of 342 pg/mL, an aldosterone-to-renin ratio of 79.5 (> 40), and 24-hr urinary aldosterone levels of 15.9 μg per day under the adequate salt-loaded condition. Adrenal venous sampling yielded aldosterone hypersecretion from the left adrenal vein, which indicated aldosterone-producing adenoma. Laparoscopic partial left adrenalectomy was performed and fully normalized ARC, PAC, and urinary aldosterone levels, which indicated biochemical cure of PA. Consequently, blood pressure had been well controlled with a single CCB. However, while her preoperative serum creatine level ranged from 0.9 to 1.1 mg/dL and eGFR was around 40–50 mL/min/1.73m2, her postoperative serum creatine level increased to 1.4 to 1.9 mg/dL and eGFR decreased to 25 to 35 mL/min/1.73m2 on average. In contrast, urinary protein level improved to less than 0.1 g/day, suggesting that post-treatment increase in creatine level indicated unveiling CKD rather than deterioration of renal function.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>PA treatment may unmask CKD through improving glomerular hyperfiltration from aldosterone excess.</jats:p> </jats:sec>

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PS-R07-3: BILATERAL ADRENAL TUMORS IN A PATIENT WITH PRIMARY ALDOSTERONISM CONCURRENT WITH CUSHING'S SYNDROME: A CASE REPORT.

Yusuke Otomo, Junichiro Irie, Kazutoshi Miyashita, Sakiko Kobayashi, Kenichiro Kinouchi, Toshifumi Nakamura, Yusuke Kubota, Takeshi Nishimura, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e510 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>Both primary aldosteronism (PA) and Cushing's syndrome (CS) cause hypertension. It is known that PA can be complicated with CS, but cases with both bilateral PA and unilateral CS are rare.</jats:p> </jats:sec> <jats:sec> <jats:title>Case presentation:</jats:title> <jats:p>A 65-year-old male patient was treated on 10 mg of amlodipine and 2 mg of doxazosin for hypertension from 6 years ago and his blood pressure was about 150/90 mm Hg on average. Because he gained 10 kg of weight over the last 6 months, he visited his primary physician. He had moon face and central obesity, and his blood examination showed the high concentrations of adrenal hormones, i.e., plasma aldosterone concentration (PAC) was 180 pg/mL and plasma renin activity (PRA) was 0.9 ng/mL/h (aldosterone-renin ratio (ARR) was 200.2), cortisol was 11.1 mcg/dL and adrenocorticotropic hormone was undetectable. The twenty-four-hour urine test showed that the greater secretion of adrenal hormones, i.e., aldosterone was 21.4 mcg/day, free cortisol was 148.5 mcg/day (sodium was 190 mEq/day). The computed tomography scan showed bilateral adrenal tumors (37 mm on the left and 8 mm on the right, respectively). The captopril challenge test, the furosemide stress test, and the 1 mg and 8 mg dexamethasone suppression tests were conducted, and he was diagnosed with both PA and CS. By adrenal scintigraphy using 131I-adosterol, high accumulation was detected in the left adrenal gland, whereas there was no accumulation in the right adrenal gland. Hence, the tumor of the left adrenal gland was likely a cortisol-secreting adrenocortical tumor. Furthermore, super-selective adrenal venous sampling indicated autonomous aldosterone secretion from bilateral adrenal glands. The patient underwent laparoscopic left adrenalectomy and the hypercortisolism was corrected. He lost 10 kg of weight 1 year after the surgery. PA remained as indicated by the blood test showing that PRA was 1.2 ng/mL/h, PAC was 347 pg/mL (ARR was 289.2). He is treated with 5 mg of esaxerenone, and his blood pressure is 130/70 mmHg on average.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Adrenal venous sampling was able to determine laterality of PA with coexisting CS.</jats:p> </jats:sec>

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PS-R04-3: A CASE OF RESISTANT HYPERTENSION

Yuya Nakajima, Junichiro Irie, Toshifumi Nakamura, Yoshinaga Kawano, Arata Ito, Kenichiro Kinouchi, Sakiko Kobayashi, Shu Meguro, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e440 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>Resistant hypertension is defined as blood pressure that remains above 140/90 mmHg despite the use of three antihypertensive medications of different classes at the maximally tolerated doses, one of which is a diuretic. It is reported that approximately 10% of patients with hypertension have resistant hypertension, but the optimal management of resistant hypertension remains to be unclear.</jats:p> </jats:sec> <jats:sec> <jats:title>Case presentation:</jats:title> <jats:p>A 56-year-old Japanese woman visited our hospital because she presented high blood pressure of about 170/100 mm Hg even after the treatment by her primary physician. She had hypertension after giving birth at age 26 and her blood pressure was about 170/100 mm Hg. She was suspected of having secondary hypertension and the laboratory and imaging examination were conducted. The functions of the adrenal gland and thyroid were normal, and the renal artery stenosis and chronic kidney disease were excluded. She did not have NSAIDs, oral contraceptives, and herbal products. Although she had been intensively treated for hypertension, she suffered from a brain hemorrhage. Her systolic blood pressure has been still not controlled appropriately by 80 mg of nifedipine, 400 mg of the combination of sacubitril/valsartan, 2.5 mg of esaxerenone, 2 mg of trichlormethiazide, and 9 mg of bisoprolol transdermal patch daily.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Because patients with resistant hypertension have a higher risk of stroke, kidney disease, and heart failure, the careful examination and intensive treatment are necessary.</jats:p> </jats:sec>

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PS-R03-7: PARTIAL ADRENALECTOMY IN A PATIENT WITH ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA: A CASE REPORT

Shunta Takebayashi, Junichiro Irie, Isao Kurihara, Sakiko Kobayashi, Kazutoshi Miyashita, Kenichiro Kinouchi, Toshifumi Nakamura, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e438 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>The standard treatment for ACTH-independent macronodular adrenal hyperplasia (AIMAH) with overt Cushing's syndrome is bilateral adrenalectomy. Here we show a case of AIMAH who underwent total adrenalectomy on one side and partial adrenalectomy on the other, resulting in the successful debulking of cortisol-secreting adrenal masses and improvement of Cushing's syndrome, yet not necessitating postoperative steroid replacement.</jats:p> </jats:sec> <jats:sec> <jats:title>Case presentation:</jats:title> <jats:p>A 74-year-old female patient with hypertension, type 2 diabetes and dyslipidemia developed edema of the legs. She visited her primary physician and was found to have lumbar vertebral compression fractures. The blood test and 24-hr urine collection revealed the plasma cortisol levels of 26.1 μg per dL, adrenocorticotropic hormone of 1.1 pg per mL, and urine free cortisol of 340 μg per day. Computed tomographic scan and adrenal scintigraphy confirmed bilateral adrenal nodules with notable tracer uptake. Diagnosis of AIMAH with Cushing's syndrome was made. Laparoscopic partial adrenalectomy, i.e., total removal of the left adrenal gland and partial removal of the right counterpart, was conducted aiming to avert from steroid replacement therapy. After the surgery, blood pressure and glycemic control were markedly improved and maintained for 4 years whilst adrenocortical functions were preserved.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Partial adrenalectomy could be an effective therapy in selected cases of AIMAH.</jats:p> </jats:sec>

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PS-R03-4: TRANSARTERIAL EMBOLIZATION, THORACIC SPINE DECOMPRESSION AND FUSION OF METASTATIC PHEOCHROMOCYTOMA: A CASE REPORT

Kenichiro Kinouchi, Yosuke Mizutani, Toshifumi Nakamura, Shintaro Yamaguchi, Koichiro Homma, Sakiko Kobayashi, Kazutoshi Miyashita, Isao Kurihara, Hirotaka Shibata, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e437 - e438 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:p>Surveillance of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma remain a fundamental problem to be solved. Here we present a 60-year-old male who visited a local clinic because of headache, sweating, malaise, and loss of body weight. Hypertension, orthostatic hypotension, along with remarkable increase in serum and urine noradrenaline, and urine metanephrine and vanillylmandelic acid were noted, and pheochromocytoma was suspected accordingly. Magnetic resonance imaging failed to reveal adrenal gland or sympathetic plexuses, yet it uncovered metastatic lesions in the liver and spine. Functional imaging study using 131I-Metaiodobenzylguanidine (MIBG) scan detected notable uptake in the spinal lesion, albeit not in the hepatic lesion. On the other hand, positron emission tomography with fluorodeoxyglucose (FDG-PET) disclosed FDG uptake both in the hepatic and spinal masses. Biopsy of the hepatic tumors revealed chromogranin A-positive clusters of cells, a finding consistent with metastatic pheochromocytoma. Transarterial embolization (TAE) of the metastatic tumors in the liver was performed for the purpose of tumor mass reduction. Additionally, TAE followed by resection of the spinal lesion was conducted. Pathological examination of the spinal tumor also showed chromogranin A-positive cells, leading to diagnosis of malignant pheochromocytoma. Crucially, TAE of the liver and spinal tumors resulted in dramatic reduction of catecholamine production, likely constituting an effective therapeutic strategy against metastatic pheochromocytoma (Homma, et al. Hypertens Res 2006). Afterwards, the patient became unable to walk because of weakness in the left leg at the age of 64. It seemed attributed to spinal cord compression from the tumor at the level of thoracic vertebrae 7. The patient underwent posterior decompression and fusion, and his muscle strength of the left leg was recovered. At the age of 65, the patient developed paralytic ileus following a surgery against metastatic tumors in the skull. In this case report, we discuss early detection of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma.</jats:p>

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PS-R03-3: INTERMITTENTLY SCANNED CONTINUOUS GLUCOSE MONITORING IN A DIFFICULT PATIENT WITH GESTATIONAL DIABETES MELLITUS AND SUBCLINICAL CUSHING'S SYNDROME: A CASE REPORT

Akihide Iwahara, Kazutoshi Sugiyama, Tami Tsuchiya, Arata Itoh, Yuya Nakajima, Yoshifumi Saisho, Kenichiro Kinouchi, Sakiko Kobayashi, Kazutoshi Miyashita, Junichiro Irie, Shu Meguro, Satoru Ikenoue, Mamoru Tanaka, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e437 2023.01

Lead author, Last author, Corresponding author,  ISSN  02636352

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<jats:p>A 41-year-old woman was admitted to the obstetrics department because of epigastric pain, nausea, and fatigue at 31 weeks of gestation. She was suspected of subclinical Cushing's syndrome based on high plasma cortisol and low ACTH levels along with an incidentally discovered tumor in the left adrenal gland 4 years prior to conception. 3 months before admission, 75 g oral glucose tolerance test yielded one point positive (81–169–174 mg/dL) and diagnosis of gestational diabetes mellitus was made. Diet and exercise therapy was started on an outpatient basis. While blood glucose control had been favorable, she discontinued visits to outpatient clinics due to difficulty in physical activity.</jats:p> <jats:p>At the time of admission, blood glucose level was running more than 200 mg/dl, and self-monitoring of blood glucose (SMBG) and insulin self-injection therapy were proposed for immediate blood glucose control accordingly. However, the patient had psychiatric symptoms that were presumably associated with delusional disorder and subclinical Cushing's syndrome. As such, she refused to implement both procedures on account of a strong fear against puncture, which caused blood glucose management difficult. Despite understanding the necessity of SMBG and potential risks to the fetus, the patient frequently expressed anxiety and could not perform SMBG. Given the difficult circumstance, intermittently scanned continuous glucose monitoring was installed to reduce invasive procedures. As a result, blood glucose levels were under good control with 0.43 U/kg of insulin per day until the delivery by cesarean section at 34 weeks of gestation. A healthy infant weighing 2442 g was delivered without complications.</jats:p> <jats:p>Here we highlight utility and efficacy of intermittently scanned continuous glucose monitoring in a difficult patient with gestational diabetes mellitus and subclinical Cushing's syndrome.</jats:p>

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PS-C22-6: PERFORMANCE OF PREDICTION ALGORITHM FOR THE SUBTYPE DIAGNOSIS OF PRIMARY ALDOSTERONISM WHICH WAS ADVOCATED IN THE JAPAN PRIMARY ALDOSTERONISM STUDY

Sakiko Kobayashi, Isao Kurihara, Kenichi Yokota, Kenichiro Kinouchi, Toshifumi Nakamura, Kazutoshi Miyashita, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e402 2023.01

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<jats:sec> <jats:title>Objective:</jats:title> <jats:p>In the part of the Japan Primary Aldosteronism Study (JPAS), the prediction algorithm for the subtype diagnosis of primary aldosteronism (PA) was advocated and published in 2018 (Umakoshi.H et.al, J Clin Endocrinol Metab, 2018, 103(3):900–908). In the algorithm, patients with PA with bilateral normal results on CT and normokalemia likely have a low prior probability of a lateral form of PA in AVS (6.2%) and could be treated medically, whereas those with unilateral visible mass on CT and presence of hypokalemia have a high probability of a lateralized form of PA in AVS (70.6%). To validate the efficacy of the algorithm, we applied the algorithm for recent PA cases in our institute, Keio University hospital.</jats:p> </jats:sec> <jats:sec> <jats:title>Patients:</jats:title> <jats:p>A total of 77 patients with PA who underwent adrenal venous sampling (AVS) between November 2018 and October 2019 were enrolled in this study. They were classified into four groups according to CT findings and potassium status. Subtype diagnosis of PA was determined by AVS.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>In our case, the prevalence for unilateral hyperaldosteronism on AVS was as follows: CT-negative with normokalemia, 7.9%; CT-positive with normokalemia, 15.4%; CT-negative with hypokalemia 22.2%, and CT-positive, 71.4%. The results were quite similar to the results in the previous report. In the algorithm, it was stated that AVS could be spared in patients with unilateral lesion on CT and hypokalemia if they were younger than 35 years, however, in our cases, there was one patient whose age was 30 with unilateral lesion on CT and hypokalemia and the AVS result of whom indicated bilateral PA. In the algorithm, it was also stated that AVS could be spared in patients with bilateral lesions on CT and normokalemia if plasma aldosterone concentration was less than 8 ng/dl and it was consistent in our cases.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Overall, the prediction algorithm for the subtype diagnosis of PA developed in JPAS could be applied well in our recent PA cases.</jats:p> </jats:sec>

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PS-BPR02-4: RENOVASCULAR HYPERTENSION FROM FIBROMUSCULAR DYSPLASIA WITHOUT ABNORMALITIES IN RENAL DOPPLER ULTRASOUND: A CASE REPORT.

Kyosuke Kato, Yosuke Mizutani, Toshifumi Nakamura, Kenichiro Kinouchi, Sakiko Kobayashi, Kazutoshi Miyashita, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e350 2023.01

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>Renovascular hypertension (RVH) is one of the most common forms of secondary hypertension, and accounts for nearly 1% of all hypertension cases. It is characterized by compromised renal perfusion pressure, resultant renin secretion, and hypokalemia due to secondary hyperaldosteronism. Arteriosclerosis is a common underlying pathogenesis in middle-aged and older adults, whilst fibromuscular dysplasia is occasionally seen in younger patients with RVH. Since cardiovascular complications are of grave concern in RVH, early detection and appropriate therapeutic intervention are particularly important. Here, we report a case of renovascular hypertension from fibromuscular dysplasia which was incidentally unveiled during close examination of an adrenal tumor.</jats:p> </jats:sec> <jats:sec> <jats:title>Case report:</jats:title> <jats:p>A 55-year-old woman was being treated for hypertension by her primary care physician. She was referred to our hospital for a thorough examination of her right ureteral stone, which necessitated a CT scan incidentally revealing an left adrenal nodule measuring 8 mm in size. Primary aldosteronism was unlikely based on the lack of renin suppression (active renin concentration, 36.5 pg/mL; plasma aldosterone levels, 263 pg/mL and aldosterone-renin ratio < 40 under treatment with nifedipine 40 mg/day. Ultrasound of the kidney demonstrated a notable difference in size between the right and left kidneys of 87 mm and 106 mm, respectively, albeit Renal Artery Doppler failed to suggest the renal artery stenosis. CT scan with contrast material revealed the remarkable irregularity and “string on beads” sign on the distal main trunk of the right renal artery. Renovascular hypertension from fibromyalgia dysplasia was suspected, and percutaneous renal artery angioplasty was performed. After the pressure gradient across the stenotic lesion (105/99 mmHg on the distal side and 125/67 mmHg on the proximal side of the renal artery) was verified, balloon dilation was applied. The procedure was successful as the pressure gradient virtually resolved (105/95 mmHg on the distal side and 109/101 mmHg on the proximal side of the renal artery). Digital subtraction angiography indeed reaffirmed improvement in blood flow.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Renovascular hypertension can go unnoticed solely based on renal Doppler Ultrasound. This was a case in which renovascular hypertension from fibromuscular dysplasia was incidentally identified in CT scan designated as a work-up for an adrenal tumor.</jats:p> </jats:sec>

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PS-BPR01-4: A CASE OF ALDOSTERONE-PRODUCING ADENOMA DIAGNOSED BY ADRENAL ARTERIOGRAPHY AND BRANCH SELECTIVE ADRENAL VENOUS SAMPLING

Masaru Nishikawa, Kenichiro Kinouchi, Sakiko Kobayashi, Kazutoshi Miyashita, Toshikazu Takeda, Masashi Tamura, Seishi Nakatsuka, Yosuke Mizutani, Yusuke Otomo, Kazuki Aoyama, Kenichi Yokota, Isao Kurihara, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e345 - e346 2023.01

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<jats:sec> <jats:title>Case report:</jats:title> <jats:p>A 43-year-old man had been followed up for hypertension and hypokalemia, but self-interrupted his hospital visits for the last four years. Based on the serum potassium level of 2.7 mEq/L, plasma aldosterone concentration of 202 pg/mL, and plasma renin activity of 1.1 ng/mL/hr, he was suspected of primary aldosteronism and was admitted to the previous hospital. A saline suppression test and a rapid ACTH stimulation test were both positive, and 24-hr urinary aldosterone level was 19 μg/day under sodium loading of 170 mEq/day, leading to the diagnosis of primary aldosteronism. Since contrast-enhanced CT showed an 8 mm-sized adenoma in the lower portion of the left adrenal gland, an aldosterone-producing adenoma was suspected and a non-segmental adrenal venous sampling (AVS) was performed. However, it yielded apparent bilateral aldosterone suppression in the main trunk of the bilateral adrenal veins, where the aldosterone-to-cortisol (A/C) ratio was lower than that in the inferior vena cava even after ACTH loading. The patient was referred to our hospital for a segmental AVS. Arteriography was first performed from the left inferior adrenal artery to confirm the outflow vessels from the adenoma. Strikingly, there was an aberrant vein which drained into the proximal segment of the left adrenal vein. CT imaging at the time of arteriography revealed, in addition to the known adenoma, a 6 mm-sized micronodule in the lateral region of the left adrenal gland, and the aberrant vein appeared to be the main outflow vessel from the micronodule. A segmental AVS was performed, and blood samples were taken from the bilateral adrenal veins including the aberrant vein and the main trunk of the left adrenal vein proximal to its confluence. The A/C ratio was highest in the aberrant vein, followed by in the main trunk of the proximal left adrenal vein, while it was markedly suppressed in other branches and the main trunk of the left adrenal vein distal to the confluence of the aberrant vein. Based on these results, the presence of aldosterone-producing adenoma in the left adrenal gland was suggested. Laparoscopic partial left adrenalectomy was performed without postoperative complications. Hypertension and hypokalemia were fully resolved afterwards.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Adrenal arteriography and segmental AVS should be considered in such cases that apparent bilateral aldosterone suppression is noted in conventional AVS in patients with clinically suspected aldosterone-producing adenoma.</jats:p> </jats:sec>

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PS-BPR01-3: DISSOCIATION OF SERUM ALDOSTERONE CONCENTRATIONS BETWEEN THE MEASUREMENT METHODS: A CASE REPORT

Takuto Torimitsu, Kenichiro Kinouchi, Kyosuke Kato, Akihide Iwahara, Takahide Kozuma, Toshifumi Nakamura, Sakiko Kobayashi, Kazuki Miyashita, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e345 2023.01

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<jats:p>A 89-year-old woman was admitted to our hospital for syncope in 20XX-13. During the hospitalization, hypertension was pointed out. Despite 4 cm left adrenal mass suggestive of myelolipoma in contrast-enhanced magnetic resonance imaging (MRI), the serum and urine hormone levels in relation to secondary hypertension was within normal limits. Diagnosis of essential hypertension was made and treatment with olmesartan and azelnidipine was begun. In 20XX-5, her blood pressure was well controlled, and serum aldosterone level and active renin concentration (ARC) were 167 pg/ml and 6.8 pg/ml, respectively. Annual computed tomography (CT) scans showed virtually the same size of the adrenal tumor over 5 years. The trend toward increase in her blood pressure prompted us to repeat a blood test in 20XX, which turned out that serum aldosterone concentration was extremely high (1144 pg/ml), while ARC was suppressed to 1.7 pg/ml. In light of positive captopril challenge test, primary aldosteronism was suspected, and she was admitted to our hospital. However, systolic blood pressure was only mildly elevated (130 mmHg), though blood pressure medication had not been changed for 5 years. In addition, serum potassium value was 4.7 mEq/L and 24-hr urinary aldosterone was merely 3.4 μg/day under the salt-loaded state, which was inconsistent with exceedingly high serum aldosterone concentration and argued against the diagnosis of primary aldosteronism. Hence, validity of the method to quantitate serum aldosterone levels was questioned. To determine serum aldosterone concentration, radioimmunoassay (RIA) was applied in 20XX-5, yet chemiluminescent enzyme immunoassay (CLEIA) has been introduced since 20XX. Strikingly, reexamination of the same serum sample discovered that serum aldosterone value of 770 pg/ml in CLEIA was equivalent to 59 pg/ml by RIA method. As such, marked dissociation seems present between the two types of assays in this particular patient. Although tendency of correlation with regard to serum aldosterone levels between the two methods have been clarified, attention needs to be paid for the exception as in this case. Thus, it is fundamental to thoroughly evaluate patients with suspected primary aldosteronism as to whether the clinical course and serum aldosterone levels are compatible, and if not, it may be necessary to change the measurement method.</jats:p>

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PS-BPC08-6: CLINICAL AND BIOCHEMICAL OUTCOMES OF PATIENTS WITH ALDOSTERONE-PRODUCING ADENOMA AFTER RADIOFREQUENCY ABLATION THERAPY AT KEIO UNIVERSITY HOSPITAL: 2022 REPORT

Takahide Kozuma, Sakiko Kobayashi, Toshifumi Nakamura, Kenichiro Kinouchi, Kenichi Yokota, Kazutoshi Miyashita, Isao Kurihara, Kei Takase, Seishi Nakatsuka, Hiroshi Itoh

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e314 2023.01

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<jats:sec> <jats:title>Objectives:</jats:title> <jats:p>Total adrenalectomy of an affected adrenal gland is the standard therapy of aldosterone-producing adenoma (APA), a curable subtype of primary aldosteronism. However, the APA is occasionally inoperable in cases with bilateral adenomas or high-risk patients under general anesthesia. Computed tomography (CT)-guided radiofrequency ablation (RFA) of the adrenal gland is a less invasive, cortical-sparing therapy, and may become a treatment of choice for such cases. A multicenter clinical trial of RFA was conducted in patients with APA in Japan from 2015 to 2016. To establish its long-term efficacy and safety, the study subjects enrolled in Keio University Hospital have been annually followed up. Following the progress report at ISH 2018, here we update clinical and biochemical outcomes of this cohort of patients 6 years after the RFA treatment.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Follow-up medical interviews, blood pressure measurements, blood tests, and urinalysis were done annually. In addition, at least one CT scan was performed since 2018. Data on antihypertensive medication, blood pressure, hormone and electrolyte levels, urinary albumin, and tumor size were collected and analyzed.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>10 cases of APA were treated with RFA between June 2015 and March 2016. As of April 2022, 6 cases were successfully followed up. Of these patients, the aldosterone-to-renin ratio (ARR) remained normalized in 5 cases (83%), albeit above the upper limit in 1 case (17%). In this particular patient, serum potassium level remained normalized and antihypertensive medication was not needed. Antihypertensive medication was needed in 1 case (17%), while urinary albumin levels were improved in all cases. Of note, follow-up CT scan showed that the tumor was undetectable in 1 case (17%), reduced in size in 3 cases (50%) and unchanged in 2 cases (33%). None of the cases have developed adrenal insufficiency since the RFA.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>The follow-up study on APA patients 6-year after the RFA revealed no cases of recurrence. RFA is likely to be effective and safe in patients with APA.</jats:p> </jats:sec>

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PS-BPB01-2: VASCULAR ENDOTHELIAL NAMPT-MEDIATED NAD+ BIOSYNTHESIS REGULATES WHOLE-BODY BLOOD PRESSURE AND INSULIN RESISTANCE

Shotaro Kosugi, Shintaro Yamaguchi, Koichiro Homma, Taichi Nagahisa, Ken Nishioka, Yasuhiro Watanabe, Kenichiro Kinouchi, Kaori Hayashi, Kazutoshi Miyasita, Takeshi Kanda, Junichiro Irie, Jun Yoshino, Hiroshi Ito

Journal of Hypertension (Ovid Technologies (Wolters Kluwer Health))  41   e264 2023.01

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<jats:sec> <jats:title/> <jats:p>Obesity is associated with dysregulation in blood pressure control and whole-body glucose metabolism, but the precise underlying mechanism(s) remain unclear. Here, we generated and characterized mice with vascular endothelial-cell specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD<jats:sup>+</jats:sup>), a key regulator of cellular energy metabolism. We found that vascular endothelial cell-specific <jats:italic toggle="yes">Nampt</jats:italic> knockout (VeNKO) mice exhibited 1) higher blood pressure (systolic blood pressure; flox/flox mice: 111 ± 2.6 mmHg, VeNKO mice: 134 ± 4.0 mmHg, p < 0.05) with cardiac hypertrophy (flox/flox mice: 5.0 mg/g-body weight, VeNKO mice: 6.1 mg/g-body weight, p < 0.05) and 2) insulin resistance with abnormal fat distribution, under high-fat diet feeding. These deleterious alterations were partially rescued by administering nicotinamide mononucleotide (NMN), a key NAD<jats:sup>+</jats:sup> intermediate. Taken together, our findings demonstrate that vascular endothelial NAMPT-mediated NAD<jats:sup>+</jats:sup> biosynthesis is involved in the regulation of blood pressure and whole-body glucose metabolism. Our study provides mechanistic and therapeutic insights into vascular endothelia NAD<jats:sup>+</jats:sup> biology related to obesity-associated hypertension and insulin resistance.</jats:p> </jats:sec>

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Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus: A randomized, crossover trial

Takashi Murata, Kiminori Hosoda, Kunihiro Nishimura, Yoshihiro Miyamoto, Naoki Sakane, Noriko Satoh-Asahara, Masao Toyoda, Yushi Hirota, Munehide Matsuhisa, Akio Kuroda, Ken Kato, Ryuji Kouyama, Junnosuke Miura, Atsuhito Tone, Masato Kasahara, Shu Kasama, Shota Suzuki, Yukie Ito, Tomokazu Watanabe, Akiko Suganuma, Zhuo Shen, Hiroko Kobayashi, Satoshi Takagi, Sari Hoshina, Kanako Shimura, Yukiko Tsuchida, Moritsugu Kimura, Nobumichi Saito, Akira Shimada, Yoichi Oikawa, Atsushi Satomura, Akifumi Haisa, Satoshi Kawashima, Shu Meguro, Hiroshi Itoh, Yoshifumi Saisho, Junichiro Irie, Masami Tanaka, Masanori Mitsuishi, Yuya Nakajima, Jun Inaishi, Kenichiro Kinouchi, Shintaro Yamaguchi, Arata Itoh, Kazutoshi Sugiyama, Kazuma Yagi, Tami Tsuchiya, Noriko Kodani, Ikki Shimizu, Tetsuya Fukuda, Yoshiki Kusunoki, Tomoyuki Katsuno, Yuka Matoba, Yumi Hitaka, Kentaro Abe, Natsuko Tanaka, Ryoko Taniguchi, Toshihiko Nagao, Kazuyuki Hida, Izumi Iseda, Masaya Takeda, Yuichi Matsushita, Masafumi Tenta, Tsuyoshi Tanaka, Kunichi Kouyama, Michiru Fukunaga

Diabetes Research and Clinical Practice (Elsevier BV)  195   110147 2023.01

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We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range.This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR;70 mg/dL).The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index 5 was significantly reduced (8.6 % vs 23.7 %, P  0.001).The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM.

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術後良好な血圧コントロールが得られた先端巨大症の一例

児島 大輝, 小林 佐紀子, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 大喜多 肇, 植田 良, 宮下 和季, 伊藤 裕

日本腎臓学会誌 ((一社)日本腎臓学会)  64 ( 6-E ) 610 - 610 2022.10

Lead author, Last author, Corresponding author,  ISSN  0385-2385

2型糖尿病加療中に発見され原発不明癌の副腎転移が疑われた1例

渡辺 麻里, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 中村 俊文, 水谷 洋佑, 平田 賢郎, 伊藤 史麿, 上野 彰久, 真杉 洋平, 中塚 誠之, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 2 ) 601 - 601 2022.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

10年の経過で緩徐に増大し診断された散発性甲状腺髄様癌の一例

河本 ひかり, 小林 佐紀子, 中村 俊文, 木内 謙一郎, 宮下 和季, 水谷 洋佑, 川井田 みほ, 竹林 亜貴子, 小澤 宏之, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 2 ) 579 - 579 2022.10

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isCGMを活用し周術期血糖管理を行なった認知症合併1型糖尿病の1例

木内 謙一郎, 中島 裕也, 三石 正憲, 税所 芳文, 入江 潤一郎, 田中 正巳, 目黒 周, 伊藤 裕

糖尿病 ((一社)日本糖尿病学会)  65 ( 7 ) 394 - 394 2022.07

Lead author, Last author, Corresponding author,  ISSN  0021-437X

血糖測定の協力が得られず血糖管理に難渋したサブクリニカルクッシング症候群合併妊娠糖尿病の一例

岩原 彰秀, 渡辺 麻里, 西川 賢, 河本 ひかり, 杉山 和俊, 土屋 多美, 伊藤 新, 中島 裕也, 税所 芳史, 木内 謙一郎, 宮下 和季, 小林 佐紀子, 入江 潤一郎, 目黒 周, 池ノ上 学, 田中 守, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 368 - 368 2022.04

Lead author, Last author, Corresponding author,  ISSN  0029-0661

褐色細胞腫術後に多発性肺転移が認められ手術を施行した症例

水谷 洋佑, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 加藤 恭介, 渡辺 康博, 矢野 海斗, 大久保 裕, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 388 - 388 2022.04

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Epoprostenolによる薬剤性甲状腺中毒症の1例

加藤 恭介, 古田島 太希, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 水谷 洋佑, 高橋 利奈, 大友 佑介, 西川 賢, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 354 - 354 2022.04

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再発時に異所性ACTH症候群を指摘された嗅神経芽細胞腫に薬物療法を試みた一例

洲之内 真理愛, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 水谷 洋佑, 渡辺 康博, 加藤 恭介, 岩原 彰秀, 御子柴 卓弥, 小澤 宏之, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 405 - 405 2022.04

Lead author, Last author, Corresponding author,  ISSN  0029-0661

リンパ球性下垂体炎に伴う部分的副腎不全に妊娠中のステロイド補償を行い出産した一例

高橋 利奈, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 水谷 洋佑, 押田 卓磨, 小杉 将太郎, 青山 和樹, 竹林 駿太, 水口 雄貴, 田中 守, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 315 - 315 2022.04

Lead author, Last author, Corresponding author,  ISSN  0029-0661

右副腎にアルドステロン産生細胞クラスターが多発した、原発性アルドステロン症の一例

大友 佑介, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 水谷 洋佑, 高橋 利奈, 杉田 絵里那, 洲之内 真理愛, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  98 ( 1 ) 387 - 387 2022.04

Lead author, Last author, Corresponding author,  ISSN  0029-0661

診断と治療に難渋し最終的に甲状腺全摘術を施行したアミオダロン誘発甲状腺中毒症の1例

川合 未来, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 渡辺 康博, 青山 和樹, 押田 卓磨, 中島 裕也, 小澤 宏之, 勝俣 良紀, 大喜多 肇, 吉村 弘, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  97 ( 5 ) 1150 - 1150 2022.03

Lead author, Last author, Corresponding author,  ISSN  0029-0661

2型糖尿病で通院中に周期性のACTH上昇を指摘され診断に至ったCushing病の1例

加藤 恭介, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 税所 芳史, 横田 健一, 栗原 勲, 目黒 周, 伊藤 裕

肥満研究 ((一社)日本肥満学会)  27 ( Suppl. ) 345 - 345 2022.03

Lead author, Last author, Corresponding author,  ISSN  1343-229X

チアマゾールによる薬剤性血小板減少症が疑われたが中止後も血小板減少が遷延し、特発性血小板減少性紫斑病と診断された1例

青山 和樹, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 永山 愛子, 櫻井 政寿, 杉山 和俊, 佐々木 裕伸, 中島 裕也, 川合 未来, 洲之内 真理愛, 渡辺 康博, 乃村 元子, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  97 ( 5 ) 1139 - 1139 2022.03

Lead author, Last author, Corresponding author,  ISSN  0029-0661

抗甲状腺薬開始2週間後に熱発した高齢初発のバセドウ病患者の一例

渡辺 康博, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 洲之内 真理愛, 青山 和樹, 川合 未来, 中島 裕也, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  97 ( 5 ) 1142 - 1142 2022.03

Lead author, Last author, Corresponding author,  ISSN  0029-0661

DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation

Akihito Hishikawa, Kaori Hayashi, Akiko Kubo, Kazutoshi Miyashita, Akinori Hashiguchi, Kenichiro Kinouchi, Norifumi Yoshimoto, Ran Nakamichi, Riki Akashio, Erina Sugita, Tatsuhiko Azegami, Toshiaki Monkawa, Makoto Suematsu, Hiroshi Itoh

iScience (Elsevier BV)  24 ( 12 ) 103436 - 103436 2021.12

Lead author, Last author, Corresponding author,  ISSN  2589-0042

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The "preconditioning effect" in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

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副腎動脈造影と分枝選択的副腎静脈サンプリングにより診断に至ったアルドステロン産生腺腫の1例

西川 賢, 宮下 和季, 小林 佐紀子, 木内 謙一郎, 武田 利和, 田村 全, 中塚 誠之, 水谷 洋佑, 大友 佑介, 青山 和樹, 横田 健一, 栗原 勲, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  97 ( 4 ) 765 - 765 2021.12

Lead author, Last author, Corresponding author,  ISSN  0029-0661

膵癌に対するGEM投与によりTMAを発症した1例

竹原 与優, 安達 京華, 鳥光 拓人, 木内 謙一郎, 山口 慎太郎, 神田 武志, 門川 俊明, 伊藤 裕

日本内科学会関東地方会 (日本内科学会-関東地方会)  673回   38 - 38 2021.11

Lead author, Last author, Corresponding author

Pharmacokinetics of hydrogen after ingesting a hydrogen-rich solution: A study in pigs.

Genki Ichihara, Yoshinori Katsumata, Hidenori Moriyama, Hiroki Kitakata, Akeo Hirai, Mizuki Momoi, Seien Ko, Yoshiki Shinya, Kenichiro Kinouchi, Eiji Kobayashi, Motoaki Sano

Heliyon (Elsevier BV)  7 ( 11 ) e08359 2021.11

Lead author, Last author, Corresponding author, Accepted,  ISSN  24058440

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Drinking hydrogen (H2)-rich water is a common way to consume H2. Although many studies have shown efficacy of drinking H2-rich water in neuropsychiatric and endocrine metabolic disorders, their authenticity has been questioned because none examined the associated pharmacokinetics of H2. Therefore, we performed the first study to investigate the pharmacokinetics of H2 in pigs given an H2-rich glucose solution with the aim to extrapolate the findings to humans. We inserted blood collection catheters into the jejunal and portal veins, suprahepatic inferior vena cava, and carotid artery of 4 female pigs aged 8 weeks. Then, within 2 min we infused 500 ml of either H2-rich or H2-free glucose solution into the jejunum via a percutaneous gastrostomy tube and measured changes in H2 concentration in venous and arterial blood over 120 min. After infusion of the H2-rich glucose solution, H2 concentration in the portal vein peaked at 0.05 mg/L and remained at more than 0.016 mg/L (H2 saturation level, 1%) after 1 h; it also increased after infusion of H2-free glucose solution but remained below 0.001 mg/L (H2 saturation level, 0.06%). We assume that H2 was subsequently metabolized in the liver or eliminated via the lungs because it was not detected in the carotid artery. In conclusion, drinking highly concentrated H2-rich solution within a short time is a good way to increase H2 concentration in portal blood and supply H2 to the liver.

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術後にhungry bone症候群を伴い治療に難渋した副甲状腺癌の一例

杉田 絵里那, 小林 佐紀子, 宮下 和季, 木内 謙一郎, 高橋 利奈, 押田 卓磨, 日鼻 瑛, 小澤 宏之, 関水 真理子, 川井田 みほ, 栗原 勲, 横田 健一, 伊藤 裕

日本内分泌学会雑誌 ((一社)日本内分泌学会)  97 ( 2 ) 521 - 521 2021.10

Lead author, Last author, Corresponding author,  ISSN  0029-0661

【時間生物学の現在】副腎皮質ホルモンの概日リズムと内分泌代謝恒常性

鳥光 拓人, 木内 謙一郎, 栗原 勲, 伊藤 裕

臨床化学 ((一社)日本臨床化学会)  50 ( 4 ) 337 - 344 2021.10

Lead author, Last author, Corresponding author,  ISSN  0370-5633

【時間生物学と医療の融合-現状と将来-】エネルギー代謝・運動の日内ホメオスタシス制御の根幹を成す生体時計

木内 謙一郎, 宮下 和季, 伊藤 裕

Medical Science Digest ((株)ニュー・サイエンス社)  47 ( 8 ) 403 - 407 2021.07

Lead author, Last author, Corresponding author,  ISSN  1347-4340

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概日リズムは生体が昼夜の変化する環境に予測して適応する内分泌代謝恒常性に重要な機構である。その中心的な役割を生体時計が担っており、地球の自転に伴う太陽光の明暗による調節を受けながら、約24時間周期の行動、代謝、ホルモンなどのリズムを生み出している。哺乳類の末梢組織に存在する生体時計は食事や運動にも同調する一方で、食事や運動に対する昼夜の代謝応答を制御することも分かっている。近年の研究で組織や細胞間での時計の連携や協調が、個体のエネルギー代謝恒常性に重要であることも明らかになりつつある。(著者抄録)

濃厚な家族集積性を認める急性発症1型糖尿病の1例

木内 謙一郎, 中島 裕也, 小谷 紀子, 三石 正憲, 税所 芳史, 入江 潤一郎, 田中 正巳, 目黒 周, 伊藤 裕

糖尿病 ((一社)日本糖尿病学会)  64 ( 7 ) 421 - 421 2021.07

Lead author, Last author, Corresponding author,  ISSN  0021-437X

Combined Gene Expression and Chromatin Immunoprecipitation From a Single Mouse Hippocampus.

Jean-Christophe Helbling, Kenichiro Kinouchi, Pierre Trifilieff, Paolo Sassone-Corsi, Marie-Pierre Moisan

Current protocols (Wiley)  1 ( 2 ) e33 2021.02

Lead author, Last author, Corresponding author,  ISSN  26911299

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All neuronal cells hold the same genetic information but vary by their structural and functional plasticity depending on the brain area and environmental influences. Such variability involves specific gene regulation, which is driven by transcription factors (TFs). In the field of neuroscience, epigenetics is the main mechanism that has been investigated to understand the dynamic modulation of gene expression by behavioral responses, stress responses, memory processes, etc. Nowadays, gene expression analyzed by real-time quantitative PCR and TF binding estimated by chromatin immunoprecipitation (ChIP) enables one to dissect this regulation. Because of the wide range of transgenic models, as well as cost-effective aspects, mouse models are widely used neuroscience. Thus, we have set up a protocol that allows extraction of both RNA for gene expression analysis and chromatin for ChIP experiment from a single mouse hippocampus. Using such protocols, information regarding gene expression and regulatory molecular mechanisms from the same animal can be integrated and correlated with neurobiological and behavioral outcomes. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Hippocampus isolation from mouse brain Basic Protocol 2: RNA extraction and gene expression analysis from a mouse half hippocampus Basic Protocol 3: ChIP from one hemisphere side mouse hippocampus.

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エネルギー代謝・運動の日内ホメオスタシス制御の根幹を成す生体時計

Kinouchi Kenichiro

Medical Science Digest 47   403 - 407 2021

Lead author, Last author, Corresponding author

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副腎皮質ホルモンの概日リズムと内分泌代謝恒常性

Kinouchi Kenichiro

臨床化学 50   337 - 344 2021

Lead author, Last author, Corresponding author

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S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.

Carolina Magdalen Greco, Marlene Cervantes, Jean-Michel Fustin, Kakeru Ito, Nicholas Ceglia, Muntaha Samad, Jiejun Shi, Kevin Brian Koronowski, Ignasi Forne, Suman Ranjit, Jonathan Gaucher, Kenichiro Kinouchi, Rika Kojima, Enrico Gratton, Wei Li, Pierre Baldi, Axel Imhof, Hitoshi Okamura, Paolo Sassone-Corsi

Science advances (American Association for the Advancement of Science (AAAS))  6 ( 51 )  2020.12

Lead author, Last author, Corresponding author,  ISSN  23752548

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Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.

Welz PS, Zinna VM, Symeonidi A, Koronowski KB, Kinouchi K, Smith JG, Guillén IM, Castellanos A, Furrow S, Aragón F, Crainiciuc G, Prats N, Caballero JM, Hidalgo A, Sassone-Corsi P, Benitah SA

Cell 178 ( 4 ) 1029 2019.08

Lead author, Last author, Corresponding author,  ISSN  0092-8674

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.

Welz PS, Zinna VM, Symeonidi A, Koronowski KB, Kinouchi K, Smith JG, Guillén IM, Castellanos A, Furrow S, Aragón F, Crainiciuc G, Prats N, Benitah SA

Cell  2019.08

Lead author, Last author, Corresponding author

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SP037SIGNIFICANCE OF EPIGENETIC MODIFICATION IN THE KIDNEY FOR THE ONSET AND PERSISTENCE OF HYPERTENSION AFTER TRANSIENT SALT LOADING IN MICE

Sho Endo, Kentaro Fujii, Masaki Ryuzaki, Kenichiro Kinouchi, Aika Hagiwara, Masaaki Sato, Asuka Uto, Kazutoshi Miyashita, Hiroyuki Inoue, Hiroshi Itoh

Nephrology Dialysis Transplantation (Oxford University Press (OUP))  34 2019.06

Lead author, Last author, Corresponding author,  ISSN  09310509

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SP039HYPERTENSION-RELATED PROTEIN DEACETYLASE SIRT3 AFFECTS BLOOD PRESSURE THROUGH REGULATION OF INTESTINAL SALT ABSORPTION IN MICE

Kenichiro Kinouchi, Masaki Ryuzaki, Asuka Uto, Masaaki Sato, Kentaro Fujii, Sho Endo, Kazutoshi Miyashita, Hiroshi Itoh, Hiroyuki Inoue

Nephrology Dialysis Transplantation (Oxford University Press (OUP))  34 2019.06

Lead author, Last author, Corresponding author,  ISSN  09310509

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DISTRIBUTION OF ADENOSINE IN THE KISNEY DETERMINES LOCAL VASCULAR TONE VIA A2B ACTIVATION AND AFFECTS RENO-PROTECTION AGAINST ACUTE ISCHEMIA IN MICE

Kentaro, F; Kazutoshi, M; Akiko, K; Masaaki, S; Aika, H; Hiroyuki, I; Masaki, R; Sho, E; Asuka, U; Kenichiro, K; Makoto, S; Hiroshi, I

NEPHROLOGY DIALYSIS TRANSPLANTATION 34 2019.06

Lead author, Last author, Corresponding author,  ISSN  0931-0509

BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.

Welz PS, Zinna VM, Symeonidi A, Koronowski KB, Kinouchi K, Smith JG, Guillén IM, Castellanos A, Furrow S, Aragón F, Crainiciuc G, Prats N, Caballero JM, Hidalgo A, Sassone-Corsi P, Benitah SA

Cell 177 ( 6 ) 1436 - 1447.e12 2019.05

Lead author, Last author, Corresponding author,  ISSN  0092-8674

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis

Patrick-Simon Welz, Valentina M. Zinna, Aikaterini Symeonidi, Kevin B. Koronowski, Kenichiro Kinouchi, Jacob G. Smith, Inés Marín Guillén, Andrés Castellanos, Stephen Furrow, Ferrán Aragón, Georgiana Crainiciuc, Neus Prats, Juan Martín Caballero, Andrés Hidalgo, Paolo Sassone-Corsi, Salvador Aznar Benitah

Cell (Elsevier BV)  177 ( 6 ) 1436 - 1447.e12 2019.05

Lead author, Last author, Corresponding author,  ISSN  00928674

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Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock.

Pastore N, Vainshtein A, Herz NJ, Huynh T, Brunetti L, Klisch TJ, Mutarelli M, Annunziata P, Kinouchi K, Brunetti-Pierri N, Sassone-Corsi P, Ballabio A

The EMBO journal (Springer Science and Business Media LLC)  38 ( 12 ) e101347 2019.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0261-4189

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Light Entrains Diurnal Changes in Insulin Sensitivity of Skeletal Muscle via Ventromedial Hypothalamic Neurons.

Aras E, Ramadori G, Kinouchi K, Liu Y, Ioris RM, Brenachot X, Ljubicic S, Veyrat-Durebex C, Mannucci S, Galié M, Baldi P, Sassone-Corsi P, Coppari R

Cell reports (Elsevier BV)  27 ( 8 ) 2385 - 2398.e3 2019.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  22111247

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Defining the Independence of the Liver Circadian Clock.

Koronowski KB, Kinouchi K, Welz PS, Smith JG, Zinna VM, Shi J, Samad M, Chen S, Magnan CN, Kinchen JM, Li W, Baldi P, Benitah SA, Sassone-Corsi P

Cell (Elsevier BV)  177 ( 6 ) 1448 - 1462.e14 2019.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0092-8674

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.

Welz PS, Zinna VM, Symeonidi A, Koronowski KB, Kinouchi K, Smith JG, Guillén IM, Castellanos A, Furrow S, Aragón F, Crainiciuc G, Prats N, Benitah SA

Cell 177 ( 6 ) 1436 - 1447.e12 2019.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0092-8674

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Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle.

Kinouchi K, Magnan C, Ceglia N, Liu Y, Cervantes M, Pastore N, Huynh T, Ballabio A, Baldi P, Masri S, Sassone-Corsi P

Cell reports (Elsevier BV)  25 ( 12 ) 3299 - 3314.e6 2018.12

Lead author, Last author, Corresponding author, Accepted,  ISSN  22111247

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Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks.

Dyar KA, Lutter D, Artati A, Ceglia NJ, Liu Y, Armenta D, Jastroch M, Schneider S, de Mateo S, Cervantes M, Abbondante S, Tognini P, Orozco-Solis R, Sassone-Corsi P

Cell (Elsevier BV)  174 ( 6 ) 1571 - 1585.e11 2018.09

Lead author, Last author, Corresponding author, Accepted,  ISSN  0092-8674

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Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis

Selma Masri, Thales Papagiannakopoulos, Kenichiro Kinouchi, Yu Liu, Marlene Cervantes, Pierre Baldi, Tyler Jacks, Paolo Sassone-Corsi

CELL (Elsevier BV)  165 ( 4 ) 896 - 909 2016.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0092-8674

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Circadian clocks, epigenetics, and cancer

Selma Masri, Kenichiro Kinouchi, Paolo Sassone-Corsi

CURRENT OPINION IN ONCOLOGY (Ovid Technologies (Wolters Kluwer Health))  27 ( 1 ) 50 - 56 2015.01

Lead author, Last author, Corresponding author, Accepted,  ISSN  1040-8746

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells

Asako Kurauchi-Mito, Atsuhiro Ichihara, Kanako Bokuda, Mariyo Sakoda, Kenichiro Kinouchi, Tomonori Yaguchi, Taketo Yamada, Ge-Hong Sun-Wada, Yoh Wada, Hiroshi Itoh

Hypertension Research (Japanese Society of Hypertension)  37 ( 9 ) 830 - 835 2014.09

Lead author, Last author, Corresponding author,  ISSN  1348-4214

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells

Asako Kurauchi-Mito, Atsuhiro Ichihara, Kanako Bokuda, Mariyo Sakoda, Kenichiro Kinouchi, Tomonori Yaguchi, Taketo Yamada, Ge-Hong Sun-Wada, Yoh Wada, Hiroshi Itoh

HYPERTENSION RESEARCH 37 ( 9 ) 830 - 835 2014.09

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells.

Kurauchi-Mito A, Ichihara A, Bokuda K, Sakoda M, Kinouchi K, Yaguchi T, Yamada T, Sun-Wada GH, Wada Y, Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 37 ( 9 ) 830 - 5 2014.09

Lead author, Last author, Corresponding author,  ISSN  0916-9636

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Significant roles of the (pro)renin receptor in integrity of vascular smooth muscle cells

Asako Kurauchi-Mito, Atsuhiro Ichihara, Kanako Bokuda, Mariyo Sakoda, Kenichiro Kinouchi, Tomonori Yaguchi, Taketo Yamada, Ge-Hong Sun-Wada, Yoh Wada, Hiroshi Itoh

Hypertension Research (Springer Science and Business Media LLC)  37 ( 9 ) 830 - 835 2014.05

Lead author, Last author, Corresponding author,  ISSN  09169636

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The (pro)renin receptor ((P)RR) is known to play an important role in the pathogenesis of vascular complications in diabetes mellitus and hypertension through its function in activating the local renin-angiotensin system. Recent studies have shown that the (P)RR is an accessory protein of the vacuolar H(+)-ATPase, suggesting a more fundamental and developmental function. In this study, smooth muscle cell-specific (P)RR/Atp6ap2 conditional knockout mice were generated. Smooth muscle cell-specific ablation of the (P)RR resulted in nonatherogenic sclerosis in the abdominal aorta. The deletion of the (P)RR did not affect ambulatory blood pressure levels. In cultured murine vascular smooth muscle cells (VSMCs), ablation of the (P)RR suppressed the expression of the Vo subunit c of the vacuolar H(+)-ATPase and impaired the cell recycling system, leading to autophagic cell death. In addition, loss of the (P)RR in VSMCs induced the expression of monocyte chemotactic protein-1 and interleukin-6 mRNAs. These results suggest that the (P)RR is essential for cell survival and downregulation of vascular inflammation in murine VSMCs through maintaining normal function of the vacuolar H(+)-ATPase.

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The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H+-ATPase biogenesis

Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge-Hong Sun-Wada, Yoh Wada, Hiroki Ochi, Toru Fukuda, Kanako Bokuda, Hideaki Kurosawa, Naohiro Yoshida, Shu Takeda, Keiichi Fukuda, Hiroshi Itoh

PLoS ONE (Public Library of Science (PLoS))  8 ( 11 ) e78603 2013.11

Lead author, Last author, Corresponding author, Accepted,  ISSN  1932-6203

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The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H(+)-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the N-terminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Δ4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.

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Effects of Adding Ezetimibe to Fluvastatin on Kidney Function in Patients with Hypercholesterolemia: a Randomized Control Trial

Kenichiro Kinouchi, Atsuhiro Ichihara, Kanako Bokuda, Satoshi Morimoto, Hiroshi Itoh

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 20 ( 3 ) 245 - 256 2013

Lead author, Last author, Corresponding author, Accepted,  ISSN  1340-3478

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Current knowledge of (pro)renin receptor as an accessory protein of vacuolar H+-ATPase

Atsuhiro Ichihara, Kenichiro Kinouchi

JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (SAGE Publications)  12 ( 4 ) 638 - 640 2011.12

Lead author, Last author, Corresponding author, Accepted,  ISSN  1470-3203

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<jats:p> The (pro)renin receptor (P)RR is a receptor for renin and prorenin, not only allowing local production of angiotensin I from angiotensinogen, but also inducing intracellular signaling. Intriguingly, (P)RR is also called ATP6AP2 because a (P)RR fragment was demonstrated to be associated with vacuolar-type H+-ATPase (V-ATPase), which is of importance for the maintenance of intracellular pH. Recent studies implicate that deletion of (P)RR results in the dysfunction of V-ATPase, suggesting that the (P)RR is essential for its role as a proton pump. Furthermore, the novel function of (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, (P)RR is a multi-functional molecule with functions beyond renin and prorenin. This review focuses on the current knowledge and issues of (P)RR and V-ATPase. </jats:p>

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Prorenin Receptor Is Essential for Normal Podocyte Structure and Function

Yoichi Oshima, Kenichiro Kinouchi, Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Kanako Bokuda, Tatsuya Narita, Hideaki Kurosawa, Ge-Hong Sun-Wada, Yoh Wada, Taketo Yamada, Minoru Takemoto, Moin A. Saleem, Susan E. Quaggin, Hiroshi Itoh

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY (Ovid Technologies (Wolters Kluwer Health))  22 ( 12 ) 2203 - 2212 2011.12

Lead author, Last author, Corresponding author, Accepted,  ISSN  1046-6673

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The prorenin receptor is an accessory subunit of the vacuolar H+-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V0 c-subunit of the vacuolar H+-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.

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Functional characterization of (pro) renin receptor in association with V-ATPase

Kenichiro Kinouchi, Atsuhiro Ichihara, Hiroshi Itoh

FRONTIERS IN BIOSCIENCE-LANDMARK (IMR Press)  16 ( 8 ) 3216 - 3223 2011.06

Lead author, Last author, Corresponding author, Accepted,  ISSN  1093-9946

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The (pro)renin receptor ((P)RR) is a unique molecule that binds prorenin and renin in tissues, not only leading to their activation, but also inducing intracellular signaling. As a key player in the local renin-angiotensin system, (P)RR activation plays an important role in the development of cardiac fibrosis and proteinuria in hypertension and diabetes. Intriguingly, the fragment (P)RR is also called ATP6AP2 because it has been shown to be associated with vacuolar-type H(+)-ATPase (V-ATPase). The V-ATPase is a multi-subunit proton pump involved in diverse and fundamental cellular processes, including receptor-mediated endocytosis, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal enzymes. The role of (P)RR in the function of the V-ATPase is implicated in the previous findings and vigorously investigated in the recent studies. Furthermore, the novel function of the (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, the (P)RR is a multi-functional molecule that shows the complex structure and behaviour. This review highlights the current insights and the future perspectives in research regarding the (P)RR and mammalian V-ATPase.

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Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

Masaki Ryuzaki, Atsuhiro Ichihara, Yoichi Ohshima, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Murohashi-Bokuda, Akira Nishiyama, Hiroshi Itoh

HYPERTENSION RESEARCH (Springer Science and Business Media LLC)  34 ( 3 ) 301 - 307 2011.03

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-β mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-β mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

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(Pro)renin receptor/ATP6AP2 and cell death

Kinouchi, K. and Ichihara, A. and Ito, H.

Japanese Journal of Nephrology 53 ( 7 ) 996 - 999 2011

Lead author, Last author, Corresponding author,  ISSN  03852385

(プロ)レニン受容体/ATP6AP2と細胞死

木内 謙一郎, 市原 淳弘, 伊藤 裕

日本腎臓学会誌 = The Japanese journal of nephrology (東京 : 日本腎臓学会)  53 ( 7 ) 996 - 999 2011

Lead author, Last author, Corresponding author, Accepted,  ISSN  03852385

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コレクション : 国立国会図書館デジタルコレクション > 電子書籍・電子雑誌 > 学術機関 > 学協会

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[(Pro)renin receptor /ATP6AP2 and cell death].

Kinouchi K, Ichihara A, Ito H

Nihon Jinzo Gakkai shi (日本腎臓学会)  53 ( 7 ) 996 - 999 2011

Lead author, Last author, Corresponding author, Accepted,  ISSN  0385-2385

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Differential effects in cardiovascular markers between high-dose angiotensin II receptor blocker monotherapy and combination therapy of ARB with calcium channel blocker in hypertension (DEAR Trial)

Kenichiro Kinouchi, Atsuhiro Ichihara, Kanako Bokuda, Hideaki Kurosawa, Hiroshi Itoh

International Journal of Hypertension (Hindawi Limited)  2011   284823 - 11 2011

Lead author, Last author, Corresponding author, Accepted,  ISSN  2090-0384

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<jats:p><jats:italic>Background/Aims</jats:italic>. Arterial stiffness is an independent risk factor for cardiovascular morbidity and mortality. This study was conducted to determine the effect of olmesartan (OLM) and azelnidipine (AZL) on arterial stiffness using the cardio-ankle vascular index (CAVI), which is a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients.<jats:italic>Methods</jats:italic>. Fifty-two consecutive hypertensive patients were randomly assigned either to a group treated with OLM monotherapy or to a group treated with OLM and AZL combination therapy. Clinical and biological parameters were measured before and 12 months after the start of this study.<jats:italic>Results</jats:italic>. Both therapies significantly and similarly reduced BP, augmentation index, and plasma aldosterone levels. The combination therapy significantly decreased CAVI and serum low-density lipoprotein (LDL-C) levels and these reductions were significantly greater than those produced with monotherapy. No significant differences in metabolic parameters were observed between the two therapies.<jats:italic>Conclusion</jats:italic>. The combination therapy with OLM and AZL had beneficial effects on arterial stiffness assessed by CAVI, LDL-C, and metabolism, despite the similar BP reduction, compared with OLM monotherapy. Since these markers are known to influence the future risk of cardiovascular events, combination therapy with OLM and AZL could be a useful choice for treating hypertensive patients.</jats:p>

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ATP6ap2/(Pro)renin receptor

佐野 元昭, 木内 謙一郎, 市原 淳弘, 和田 洋

Shinzo (Japan Heart Foundation)  43 ( 5 ) 604 - 609 2011

Lead author, Last author, Corresponding author,  ISSN  0586-4488

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ATP6ATP2(pro)renin receptor is essential for the function of organella in murine cardiomycytes

K. Kinouchi, A. Ichihara, M. Sano, G.H. Sun-Wada, Y. Wada, A. Kurauchi-Mito, K. Bokuda, T. Narita, Y. Oshima, M. Sakoda, Y. Tama, H. Sato, K. Fukuda, H. Itoh

 2010.12

Lead author, Last author, Corresponding author, Accepted

New Approaches to Blockade of the Renin-Angiotensin-Aldosterone System: Characteristics and Usefulness of the Direct Renin Inhibitor Aliskiren

Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Bokuda, Hiroshi Itoh

JOURNAL OF PHARMACOLOGICAL SCIENCES 113 ( 4 ) 296 - 300 2010.08

Lead author, Last author, Corresponding author, Accepted,  ISSN  1347-8613

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The (Pro)renin receptor/ATP6AP2 is essential for vacuolar H +-ATPase assembly in murine cardiomyocytes

Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge-Hong Sun-Wada, Yoh Wada, Asako Kurauchi-Mito, Kanako Bokuda, Tatsuya Narita, Yoichi Oshima, Mariyo Sakoda, Yoshitaka Tamai, Hiromu Sato, Keiichi Fukuda, Hiroshi Itoh

Circulation Research (Ovid Technologies (Wolters Kluwer Health))  107 ( 1 ) 30 - 34 2010.07

Lead author, Last author, Corresponding author,  ISSN  0009-7330

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<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Rationale</jats:underline>
:
</jats:italic>
</jats:bold>
The (pro)renin receptor [(P)RR], encoded in
<jats:italic>ATP6AP2</jats:italic>
, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H
<jats:sup>+</jats:sup>
-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Objective</jats:underline>
:
</jats:italic>
</jats:bold>
We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Methods and Results</jats:underline>
:
</jats:italic>
</jats:bold>
Cardiomyocyte-specific ablation of
<jats:italic>Atp6ap2</jats:italic>
resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of
<jats:italic>Atp6ap2</jats:italic>
selectively suppressed expression of the V
<jats:sub>O</jats:sub>
subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes.
</jats:p>
<jats:p>
<jats:bold>
<jats:italic>
<jats:underline>Conclusions</jats:underline>
:
</jats:italic>
</jats:bold>
Genetic ablation of
<jats:italic>Atp6ap2</jats:italic>
created a loss-of-function model for V-ATPase. The gene product of
<jats:italic>ATP6AP2</jats:italic>
is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.
</jats:p>

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Add-on blockade of (pro)renin receptor in imidapril-treated diabetic SHRsp

Yasufumi Seki, Atsuhiro Ichihara, Yuki Mizuguchi, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Bokuda, Hiroshi Itoh

Frontiers in Bioscience - Elite 2 ( 3 ) 972 - 979 2010.06

Lead author, Last author, Corresponding author, Accepted,  ISSN  1945-0494

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Aliskiren Inhibits Intracellular Angiotensin II Levels Without Affecting (Pro)renin Receptor Signals in Human Podocytes

Mariyo Sakoda, Atsuhiro Ichihara, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Murohashi-Bokuda, Moin A. Saleem, Akira Nishiyama, Fumiaki Suzuki, Hiroshi Itoh

AMERICAN JOURNAL OF HYPERTENSION 23 ( 5 ) 575 - 580 2010.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0895-7061

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats.

Mizuguchi Y, Ichihara A, Seki Y, Sakoda M, Kurauchi-Mito A, Narita T, Kinouchi K, Bokuda K, Itoh H

Clinical and experimental pharmacology & physiology 37 ( 5-6 ) 569 - 73 2010.05

Lead author, Last author, Corresponding author,  ISSN  0305-1870

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Yuki Mizuguchi, Atsuhiro Ichihara, Yasufumi Seki, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Bokuda, Hiroshi Itoh

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 37 ( 5-6 ) 569 - 573 2010.05

Lead author, Last author, Corresponding author, Accepted,  ISSN  0305-1870

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Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats

Kenichiro Kinouchi, Asako Kurauchi-Mito, Mariyo Sakoda, Yasufumi Seki, Yuki Mizuguchi, Kanako Bokuda, Tatsuya Narita, Atsuhiro Ichihara, Hiroshi Itoh

Clinical and Experimental Pharmacology and Physiology (Wiley)  37   569 - 573 2010.04

Lead author, Last author, Corresponding author,  ISSN  03051870

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<jats:title>Summary</jats:title><jats:p>1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high‐sodium (8% NaCl) diet and heminephrectomy on PAC were examined.</jats:p><jats:p>2. Feeding of the high‐sodium diet for 12 weeks similarly decreased PAC in TG and wild‐type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high‐sodium diet, but had no effect on PAC in WT rats fed a high‐sodium diet.</jats:p><jats:p>3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high‐sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not.</jats:p><jats:p>4. Nephrin and podocin mRNA levels, as determined by real‐time quantitative reverse transcription–polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)‐1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO‐1 mRNA levels in TG rats.</jats:p><jats:p>5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.</jats:p>

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Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Murohashi-Bokuda, Hiroshi Itoh

HYPERTENSION RESEARCH (Springer Science and Business Media LLC)  33 ( 3 ) 177 - 180 2010.03

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology.

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Recent advance in (Pro)renin receptor research

Atsuhiro Ichihara, Mariyo Sakoda, Asako Mito, Tatsuya Narita, Kenichiro Kinouchi, Kanako Bokuda, Hiroshi Itoh

Respiration and Circulation (株式会社医学書院)  58 ( 3 ) 245 - 251 2010.03

Lead author, Last author, Corresponding author,  ISSN  0452-3458

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Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome

Kanako Bokuda, Atsuhiro Ichihara, Mariyo Sakoda, Asako Mito, Kenichiro Kinouchi, Hiroshi Itoh

Vascular Health and Risk Management 6 ( 1 ) 571 - 578 2010

Lead author, Last author, Corresponding author, Accepted,  ISSN  1176-6344

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Effects of Telmisartan on Arterial Stiffness Assessed by the Cardio-Ankle Vascular Index in Hypertensive Patients

Kenichiro Kinouchi, Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Kanako Murohashi-Bokuda, Hiroshi Itoh

KIDNEY & BLOOD PRESSURE RESEARCH (S. Karger AG)  33 ( 4 ) 304 - 312 2010

Lead author, Last author, Corresponding author, Accepted,  ISSN  1420-4096

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<jats:p><i>Background/Aims:</i> This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. <i>Methods:</i> One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. <i>Results:</i> CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. <i>Conclusion:</i> Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.</jats:p>

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Safety and benefits of a tablet combining losartan and hydrochlorothiazide in Japanese diabetic patients with hypertension

Kenichiro Kinouchi, Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Hiroshi Itoh

HYPERTENSION RESEARCH (Springer Science and Business Media LLC)  32 ( 12 ) 1143 - 1147 2009.12

Lead author, Last author, Corresponding author, Accepted,  ISSN  0916-9636

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This study was conducted to determine the effects of a tablet combining losartan/hydrochlorothiazide (L/HCTZ) in comparison with losartan alone in Japanese diabetic patients with hypertension. Thirty consecutive Japanese diabetic patients with hypertension were randomly assigned to group A, receiving losartan alone for the first 3 months, then L/HCTZ for the next 3 months, or group B, receiving L/HCTZ for the first 3 months, then losartan alone for the next 3 months. Clinical and biological parameters were obtained before, and 3 and 6 months after the start of this study. The decreases in systolic and diastolic blood pressure (BP) during treatment with L/HCTZ were significantly greater than in treatment with losartan alone. Both treatments significantly and similarly decreased urinary albumin excretion, the cardio-ankle vascular index (CAVI) and augmentation index (AI). There was no significant difference in metabolic change during both the mono- and combination pharmacotherapies. The tablet combining L/HCTZ significantly reduced systolic and diastolic BP compared with the losartan monotherapy, and offered benefits similar to losartan monotherapy for albuminuria, arterial stiffness assessed by the CAVI and AI, and metabolic effects. Thus, the L/HCTZ tablet could be a useful drug for Japanese diabetic patients with hypertension.

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Cell signalling and cell growth control - 2

Rui Ding, Yih-Shou Hsieh, Mohamed Samai, José M. López-Novoa, Adriana Dusso, Shigeyoshi Oba, Silvia Berra, Ying-Sui Sun, Fabien Tourrel, Luís Coentrão, Dominique Guerrot, Wanja Bernhardt, Sandra M. Sancho-Martinez, Kai-Uwe Eckardt, Christina Warnecke, Prabal K. Chatterjee, Nan Chen, Jochen Reiser, Weiping Liu, Kunimasa Yan, Yuanmeng Jin, Thomas Hackenbeck, Alina Mihaela Sburlan (Stanigut), Moin A. Saleem, Toshiro Fujita, Jiri Moravec, Yaremi Quiros, Yasunobu Hirata, Atushiro Ichihara, Victoriya A. Rufanova, Maria Pia Rasaldi, Deborah Mattinzoli, Masayuki Yoshida, Olga Surdu, Biju Marath, Sandra M. Sancho-Martínez, Piergiorgio Messa, Anna Greka, Ondrej Hes, Deborah Jane Mason, Daniel Álvarez-Hernández, Daniela Riccardi, Jan Mares, Maria Vittoria Arcidiacono, Wen Chih Chiang, Dianne Z. Hillyard, Sandra Mattauch, Kyung Pyo Kang, Thorsten Cramer, Sung Kyew Kang, Alejandro Esteller, Maria Pia Rastaldi, Martin Sachs, Maki Sunada, Bo Fu, Michael Wiesener, Andrey Sorokin, Duk Hoon Kim, João S. Amaral, Sung Kwang Park, Kerstin Amann, Doina Tofolean, Patrício Soares-da-Silva, Masanori Tokumoto, Alessandro Corbelli, Carole Elford, Yoshihiro Akimoto, Florea Voinea, Yukino Nishibori, Horng-Rong Chang, Yu Jin Jung, Alan G. Jardine, Christoph Wehrbein, Elias N. Katsoulieris, Tatusya Narita, Xue-Yuan Bai, Anna Alexanian, Ryota Kurayama, Falei Zheng, Masami Ikehata, Irene C. Green, Fang Zhong, Liliana Tuta, Won Kim, Lavinia Voineagu, Laura Giardino, Jung Eun Lee, Hideyuki Negoro, Johannes Schoedel, Arnolt J. Ramos, Wanja M. Bernhardt, Omar García-Sánchez, Ya Li, Kosaku Nitta, Sang Yong Lee, Manal J. Natto, Bronwen Alice James Evans, Michael S. Wiesener, Karl X. Knaup, Yingjuan Zhang, Ray K. Wan, Ae Sin Lee, Jun Ino, Milan Stengl, Min Li, Hui Chen, Maria João Pinho, Hiroshi Itho, Li Zhuo, Nadine Rohwer, Jong-Da Lian, Etsu Suzuki, Alena Hricinova, Cristina Zennaro, Shun-Fa Yang, Kenichiro Kinouchi, Jing Yang, Sik Lee, Guangyan Cai, Rebeca Nunez-Lozano, Yongxi Chen, Silvia Armelloni, Xiangmei Chen, Noriko Ito, Lin Han, Mariyo Sakoda, Weiming Wang, Francisco J. López-Hernández, Yaoguo Lian, Jon G. Mabley, Juergen Behrens, Chiari Kojima, Michele Carraro, Asako Kurauchi-Mito, Quan Hong

NDT Plus (Oxford University Press (OUP))  2   ii1 - ii1 2009.01

Lead author, Last author, Corresponding author,  ISSN  17530784

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Drug Discovery for Overcoming Chronic Kidney Disease (CKD): New Therapy for CKD by a (Pro)Renin-Receptor-Blocking Decoy Peptide

Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Hiroshi Itoh

JOURNAL OF PHARMACOLOGICAL SCIENCES 109 ( 1 ) 20 - 23 2009.01

Lead author, Last author, Corresponding author, Accepted,  ISSN  1347-8613

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Add-On Benefits of Amlodipine and Thiazide in Nondiabetic Chronic Kidney Disease Stage 1/2 Patients Treated with Valsartan

Yuki Kaneshiro, Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Kenichiro Kinouchi, Hiroshi Itoh

KIDNEY & BLOOD PRESSURE RESEARCH (S. Karger AG)  32 ( 1 ) 51 - 58 2009

Lead author, Last author, Corresponding author, Accepted,  ISSN  1420-4096

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<jats:p>Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.</jats:p>

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Association of (Pro)renin Receptor mRNA Expression with Angiotensin-Converting Enzyme mRNA Expression in Human Artery

Tomoko Takemitsu, Atsuhiro Ichihara, Yuki Kaneshiro, Mariyo Sakoda, Asako Kurauchi-Mito, Tatsuya Narita, Kenichiro Kinouchi, Norimasa Yamashita, Hiroshi Itoh

AMERICAN JOURNAL OF NEPHROLOGY (S. Karger AG)  30 ( 4 ) 361 - 370 2009

Lead author, Last author, Corresponding author, Accepted,  ISSN  0250-8095

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<jats:p><i>Background/Aims:</i> A significant role of (pro)renin receptor in the pathogenesis of end-organ damage has been suggested only in animal studies. This study was conducted to examine the mRNA expression of (pro)renin receptor in human artery. <i>Methods:</i> In 141 kidney failure patients, the mRNA was harvested from arterial fragments obtained during surgery constructing an arteriovenous access for hemodialysis therapy, and expression levels of (pro)renin receptor and other components of the renin-angiotensin system were determined. <i>Results:</i> Arterial (pro)renin receptor expression was similar in diabetic and non-diabetic patients, although plasma prorenin levels were significantly higher in the diabetic patients than in the non-diabetic patients. The arterial (pro)renin receptor mRNA levels of the hypertensive patients, who had not been treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers, were significantly lower than those of the patients who had been treated with either drug. Multiple regression analyses showed a significant association with a large coefficient between the arterial mRNA level of the (pro)renin receptor and the arterial mRNA level of ACE; this significant association disappeared in patients who had been treated with either drug. <i>Conclusion:</i> (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.</jats:p>

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