Papers - Yamaguchi, Shintaro

Development of Alveolar Hemorrhage After Pfizer-BioNTech COVID-19 mRNA Vaccination in a Patient With Renal-Limited Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report

Nishioka K., Yamaguchi S., Yasuda I., Yoshimoto N., Kojima D., Kaneko K., Aso M., Nagasaka T., Yoshida E., Uchiyama K., Tajima T., Yoshino J., Yoshida T., Kanda T., Itoh H.

Frontiers in Medicine (Frontiers in Medicine)  9 2022.04

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Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

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Circadian transcription factor NPAS2 and the NAD(+) -dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward

Becker-Krail, D. D., Parekh, P. K., Ketchesin, K. D., Yamaguchi, S., Yoshino, J., Hildebrand, M. A., Dunham, B., Ganapathiraju, M. K., Logan, R. W. and McClung, C. A.

Eur J Neurosci (European Journal of Neuroscience)  55 ( 3 ) 675 - 693 2022

Accepted,  ISSN  0953816X

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Substance use disorders are associated with disruptions to both circadian rhythms and cellular metabolic state. At the molecular level, the circadian molecular clock and cellular metabolic state may be interconnected through interactions with the nicotinamide adenine dinucleotide (NAD(+) )-dependent deacetylase, sirtuin 1 (SIRT1). In the nucleus accumbens (NAc), a region important for reward, both SIRT1 and the circadian transcription factor neuronal PAS domain protein 2 (NPAS2) are highly enriched, and both are regulated by the metabolic cofactor NAD(+) . Substances of abuse, like cocaine, greatly disrupt cellular metabolism and promote oxidative stress; however, their effects on NAD(+) in the brain remain unclear. Interestingly, cocaine also induces NAc expression of both NPAS2 and SIRT1, and both have independently been shown to regulate cocaine reward in mice. However, whether NPAS2 and SIRT1 interact in the NAc and/or whether together they regulate reward is unknown. Here, we demonstrate diurnal expression of Npas2, Sirt1 and NAD(+) in the NAc, which is altered by cocaine-induced upregulation. Additionally, co-immunoprecipitation reveals NPAS2 and SIRT1 interact in the NAc, and cross-analysis of NPAS2 and SIRT1 chromatin immunoprecipitation sequencing reveals several reward-relevant and metabolic-related pathways enriched among shared gene targets. Notably, NAc-specific Npas2 knock-down or a functional Npas2 mutation in mice attenuates SIRT1-mediated increases in cocaine preference. Together, our data reveal an interaction between NPAS2 and SIRT1 in the NAc, which may serve to integrate cocaine's effects on circadian and metabolic factors, leading to regulation of drug reward.

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Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility

Franczyk, M. P., Qi, N., Stromsdorfer, K. L., Li, C., Yamaguchi, S., Itoh, H., Yoshino, M., Sasaki, Y., Brookheart, R. T., Finck, B. N., DeBosch, B. J., Klein, S. and Yoshino, J.

Endocrinology 162 ( 3 )  2021.01

ISSN  0013-7227

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Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

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A case of cerebral infarction caused by painless acute aortic dissection in autosomal dominant polycystic kidney disease

Yamaguchi, S., Wakino, S., Tokuyama, H. and Itoh, H.

CEN Case Rep (CEN case reports)  9 ( 2 ) 177 - 181 2020.05

ISSN  2192-4449

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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, characterized by the progressive formation of renal cysts. Although ADPKD is strongly associated with cerebral and cardiovascular complications, cerebral ischemia caused by dissection of thoracic and carotid arteries has rarely been reported. We report the case of a 71-year-old Japanese woman who complained of hemiparesis. She required maintenance hemodialysis therapy with a background of ADPKD. Cerebral infarction was initially diagnosed by excluding intracranial hemorrhage and aneurysm rupture that are recognized as common complications of ADPKD and thereby anticoagulation therapy was initiated. However, the patient was suspected as having painless aortic dissection because a chest X-ray examination showed expanded upper mediastinum. Sequential vascular imagings revealed dissection of the aorta, originating from brachiocephalic trunk to the right common carotid artery with mediastinal hematoma. The patient died from progression of dissection. Herein, we described a case of the ADPKD patient that an acute aortic dissection without any pain induced the occlusion of supplying vessels to the brain, resulting in cerebral ischemic symptoms. A high level of clinical vigilance for an acute aortic dissection should be maintained in the ADPKD population with sudden onset of neurological symptoms even in the absence of pain. Furthermore, the initiation of anticoagulation treatment for cerebral ischemia which may aggravate the risk of further dissection requires careful consideration.

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Potential significance of Nad+ biology translational research in super-aged Japan

Yamaguchi, Shintaro, Ito, Yutaka and Yoshino, Jun

Japanese Journal of Geriatrics 57 ( 3 ) 213 - 223 2020

ISSN  0300-9173

Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors

Hiratsuka, K., Monkawa, T., Akiyama, T., Nakatake, Y., Oda, M., Goparaju, S. K., Kimura, H., Chikazawa-Nohtomi, N., Sato, S., Ishiguro, K., Yamaguchi, S., Suzuki, S., Morizane, R., Ko, S. B. H., Itoh, H. and Ko, M. S. H.

Sci Rep (Scientific Reports)  9 ( 1 ) 913 2019.12

ISSN  2045-2322

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The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2(+)SALL1(+) nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8(+)LHX1(+) pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.

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Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

Futatsugi, Koji, Tokuyama, Hirobumi, Shibata, Shinsuke, Naitoh, Makiko, Kanda, Takeshi, Minakuchi, Hitoshi, Yamaguchi, Shintaro, Hayashi, Koichi, Minamishima, Yoji Andrew, Yanagita, Motoko, Wakino, Shu, Itoh, Hiroshi

SCIENTIFIC REPORTS 6   36533 2016.11

Research paper (scientific journal), Joint Work,  ISSN  2045-2322

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The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.

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miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype

Morizane, Ryuji, Fujii, Shizuka, Monkawa, Toshiaki, Hiratsuka, Ken, Yamaguchi, Shintaro, Homma, Koichiro, Itoh, Hiroshi

CLINICAL AND EXPERIMENTAL NEPHROLOGY 20 ( 3 ) 394 - 401 2016.06

Research paper (scientific journal), Joint Work,  ISSN  1342-1751

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BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

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The pathophysiological importance and therapeutic potential of NAD'biosynthesis and mitochondrial sirtuin SIRT3 in age-associated diseases

Yamaguchi, Shintaro and Yoshino, Jun

Nihon rinsho. Japanese Journal of Clinical Medicine 74 ( 9 ) 1447 - 1455 2016

ISSN  0047-1852

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis

Yamaguchi, Shintaro, Maruyama, Tatsuya, Wakino, Shu, Tokuyama, Hirobumi, Hashiguchi, Akinori, Tada, Shinichiro, Homma, Koichiro, Monkawa, Toshiaki, Thomas, James, Miyashita, Kazutoshi, Kurihara, Isao, Yoshida, Tadashi, Konishi, Konosuke, Hayashi, Koichi, Hayashi, Matsuhiko, Itoh, Hiroshi

BMC NEPHROLOGY 16   394 - 401 2015.11

Research paper (scientific journal), Joint Work,  ISSN  1471-2369

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BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

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[The pathophysiological importance and therapeutic potential of NAD+ biosynthesis in age-related diseases]

Yamaguchi, S. and Yoshino, J.

Seikagaku 87 ( 2 ) 239 - 44 2015.04

ISSN  0037-1017

miR-34c attenuates epithelial-mesenchymal transition and kidney fibrosis with ureteral obstruction

Morizane, Ryuji, Fujii, Shizuka, Monkawa, Toshiaki, Hiratsuka, Ken, Yamaguchi, Shintaro, Homma, Koichiro, Itoh, Hiroshi

SCIENTIFIC REPORTS 4   394 - 401 2014.04

Research paper (scientific journal), Joint Work,  ISSN  2045-2322

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micro RNAs (miRNAs) are small non-coding RNAs that act as posttranscriptional repressors by binding to the 3'-UTR of target mRNAs. On the other hand, mesenchymal-epithelial transition (EMT) and kidney fibrosis is a pathological process of chronic kidney disease (CKD), and its relationship to miRNAs is becoming recognized as a potential target for CKD therapies. To find new miRNAs involved in EMT, we examined miRNA expression in experimental models of EMT and renal epithelialization using microarray, and found that miR-34c attenuates EMT induced by TGF-β in a mouse tubular cell line. To confirm the effects of miR-34c in vivo, we administered the precursor of miR-34c to mice with unilateral ureteral obstruction, and miR-34c decreased kidney fibrosis area and the expression of connective tissue growth factor, α-SMA, collagen type 1, collagen type 3 and fibronectin. In conclusion, our study showed miR-34c attenuates EMT and kidney fibrosis of mice with ureteral obstruction.

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Kidney Specific Protein-Positive Cells Derived from Embryonic Stem Cells Reproduce Tubular Structures In Vitro and Differentiate into Renal Tubular Cells

Morizane, Ryuji, Monkawa, Toshiaki, Fujii, Shizuka, Yamaguchi, Shintaro, Homma, Koichiro, Matsuzaki, Yumi, Okano, Hideyuki, Itoh, Hiroshi

PLOS ONE 8 ( 6 ) 394 - 401 2013.06

Research paper (scientific journal), Joint Work,  ISSN  1932-6203

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Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti-KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies.

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Renal microcirculation and calcium channel subtypes

Homma, Koichiro, Hayashi, Koichi, Yamaguchi, Shintaro, Fujishima, Seitaro, Hori, Shingo and Itoh, Hiroshi

Current hypertension reviews 9 ( 3 ) 182 - 186 2013

ISSN  1573-4021

Triglyceride-rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Koichiro Homma, Yasuhiko Homma, Shintaro Yamaguchi, Yutaka Shiina, Shu Wakino, Koichi Hayashi, Shingo Hori, Hiroshi Itoh.

Int J Clin Pract 66 ( 4 ) 394 - 398 2012

Research paper (scientific journal), Joint Work

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Triglyceride‐rich lipoproteins in chronic kidney disease patients undergoing maintenance haemodialysis treatment

Homma, K, Homma, Y, Yamaguchi, S, Shiina, Y, Wakino, Shu, Hayashi, Koichi, Hori, Shingo and Itoh, H

International journal of clinical practice 66 ( 4 ) 394 - 398 2012

ISSN  1368-5031

Gastrointestinal pseudo-obstruction after debulking surgery of malignant pheochromocytoma, improved by intravenous administration of alpha-adrenergic receptor blocker, phentolamine

Yamaguchi, Shintaro, Shibata, Hirotaka, Miyashita, Kazutoshi, Kurihara, Isao, Murai-Takeda, Ayano, Mitsuishi, Yuko, Motosugi, Yuichiro, Saito, Yoshimasa, Hayashi, Koichi, Itoh, Hiroshi

HYPERTENSION RESEARCH 33 ( 7 ) 753 - 754 2010.07

Research paper (scientific journal), Joint Work,  ISSN  0916-9636

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