論文 - 伊藤　裕

Relation of blood pressure quantitative trait locus on rat chromosome 1 to hyperactivity of rostral ventrolateral medulla

Iigaya, K., Kumagai, H., Nabika, T., Harada, Y., Onimaru, H., Oshima, N., Takimoto, C., Kamayachi, T., Saruta, T. and Itoh, H.

Hypertension 53 （ 1 ） 42 - 8 2009年01月

ISSN  0194-911

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Genetic factors that induce essential hypertension have been examined using genome-wide linkage analyses. A quantitative trait locus (QTL) region that is closely linked to hypertension has been found on chromosome 1 in stroke-prone spontaneously hypertensive rats (SHRSPs). We used 2 congenic rats in which the blood pressure QTL on rat chromosome 1 was introgressed from SHRSP/Izm to Wistar-Kyoto (WKY)/Izm (WKYpch1.0) and from WKY/Izm to SHRSP/Izm (SHRSPwch1.0) rats by repeated backcrossing. Previous studies reported that the intermediate phenotype of this QTL for hypertension is characterized by the hyperactivity of the sympathetic nervous system in response to physiological and psychological stress. We performed intracellular patch-clamp recordings of rostral ventrolateral medulla (RVLM) neurons from WKY, WKYpch1.0, SHRSPwch1.0, and SHRSPs and compared the basal electrophysiological activities of RVLM neurons and the responses of these neurons to angiotensin II. The basal membrane potential of RVLM neurons from WKYpch1.0 was significantly "shallower" than that of the neurons from WKY. The depolarization of RVLM neurons from WKYpch1.0 in response to angiotensin II was significantly larger than that in neurons from WKY rats, whereas the depolarization of RVLM neurons from SHRSPwch1.0 was significantly smaller than that in neurons from SHRSPs. The response to angiotensin II of RVLM neurons from WKYpch1.0 and SHRSPs was sustained even after the blockade of all of the synaptic transmissions using tetrodotoxin. The QTL on rat chromosome 1 was primarily related to the postsynaptic response of RVLM bulbospinal neurons to brain angiotensin II, whereas both the QTL and other genomic regions influenced the basal activity of RVLM neurons.

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Add-on benefits of amlodipine and thiazide in nondiabetic chronic kidney disease stage 1/2 patients treated with valsartan

Kaneshiro, Y., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Kinouchi, K. and Itoh, H.

Kidney Blood Press Res 32 （ 1 ） 51 - 8 2009年

ISSN  1420-4096

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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.

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Association of (pro)renin receptor mRNA expression with angiotensin-converting enzyme mRNA expression in human artery

Takemitsu, T., Ichihara, A., Kaneshiro, Y., Sakoda, M., Kurauchi-Mito, A., Narita, T., Kinouchi, K., Yamashita, N. and Itoh, H.

Am J Nephrol 30 （ 4 ） 361 - 70 2009年

ISSN  0250-8095

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BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: (Pro)renin receptor may contribute to the generation of arterial angiotensin II in kidney failure patients.

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(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system

Satofuka, S., Ichihara, A., Nagai, N., Noda, K., Ozawa, Y., Fukamizu, A., Tsubota, K., Itoh, H., Oike, Y. and Ishida, S.

Am J Pathol 173 （ 6 ） 1911 - 8 2008年12月

ISSN  0002-9440

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The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.

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Eradication of Helicobactor pylori may trigger onset of type 1 diabetes: a case report

Tada, A., Komiya, N., Shimada, A., Katsuki, T., Oikawa, Y. and Itoh, H.

Ann N Y Acad Sci 1150   208 - 9 2008年12月

ISSN  0077-8923

　概要を見る

In patients with idiopathic thrombocytopenic purpura (ITP), which is considered an autoimmune disease, eradication of Helicobacter pylori cures a significant number of patients. However, here we report an adult patient who developed type 1 diabetes (T1D), which is also considered an autoimmune disease, after eradication of Helicobacter pylori. Although further investigation is needed to understand the pathophysiology of T1D, we would like to emphasize that clinicians should consider the risk of its development after eradication of Helicobactor pylori.

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Activated prorenin as a therapeutic target for diabetic nephropathy

Ichihara, A., Sakoda, M., Mito-Kurauchi, A. and Itoh, H.

Diabetes Res Clin Pract 82 Suppl 1   S63 - 6 2008年11月

ISSN  0168-8227

　概要を見る

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.

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Cardio-ankle vascular index and ankle pulse wave velocity as a marker of arterial fibrosis in kidney failure treated by hemodialysis

Ichihara, A., Yamashita, N., Takemitsu, T., Kaneshiro, Y., Sakoda, M., Kurauchi-Mito, A. and Itoh, H.

Am J Kidney Dis 52 （ 5 ） 947 - 55 2008年11月

ISSN  0272-6386

　概要を見る

BACKGROUND: Patients with kidney failure treated with hemodialysis have a high incidence of cardiovascular diseases caused by accelerated arteriosclerosis. However, accurate evaluation of the extent of arteriosclerosis is difficult. This study sought to compare the strength of predictions of arterial fibrosis by using a new parameter, the cardio-ankle vascular index (CAVI), versus pulse wave velocity (PWV) in patients with kidney failure treated with hemodialysis. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 103 patients with kidney failure undergoing surgical construction of an arteriovenous access for hemodialysis therapy. INDEX TEST: CAVI and PWV. REFERENCE TEST: Arterial fibrosis, evaluated by using Masson trichrome stain on part of the brachial artery obtained during surgery, expressed as percentage of fibrosis of the layer of vascular smooth muscle cells. RESULTS: Median percentage of arterial stiffness was 52.85%. Mean PWV and CAVI were 18.3 +/- 5.6 (SD) m/s and 9.9 +/- 2.6, respectively. Multivariate regression analysis showed that arterial fibrosis was significantly associated with older age (0.247%/y; 95% confidence interval, 0.013 to 0.482) and CAVI (6.117%/unit; 95% confidence interval, 4.764 to 4.740), but not with systolic blood pressure (0.039%/mm Hg; 95% confidence interval, -0.076 to 0.153) or PWV (-0.044%/m/s; 95% confidence interval, -0.646 to 0.558). The area under the receiver operating characteristic curve to predict greater than median percentage of arterial stiffness was 0.892 for CAVI and 0.779 for PWV (P = 0.006). LIMITATION: It is unclear whether arterial fibrosis of the brachial artery evaluated by using CAVI is applicable for arteriosclerosis of other arterial districts, and clinical outcomes were not evaluated in this study. CONCLUSION: CAVI reflects the histological arterial fibrosis of hemodialysis patients and is a useful clinical marker for evaluating arterial stiffness in these patients.

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Effects of 12-month valsartan therapy on glycation and oxidative stress markers in type 2 diabetic subjects with hypertension

Komiya, N., Hirose, H., Saisho, Y., Saito, I. and Itoh, H.

Int Heart J 49 （ 6 ） 681 - 9 2008年11月

ISSN  1349-2365

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Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

The short treatment with the angiotensin receptor blocker candesartan surveyed by telemedicine (STAR CAST) study: rationale and study design

Sasamura, H., Nakaya, H., Julius, S., Takebayashi, T., Sato, Y., Uno, H., Takeuchi, M., Ishiguro, K., Murakami, M., Ryuzaki, M. and Itoh, H.

Hypertens Res 31 （ 10 ） 1843 - 9 2008年10月

ISSN  0916-9636

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Previous studies have shown that transient treatment of animal models of hypertension with an angiotensin receptor blocker (ARB) causes a sustained decrease in blood pressure values that persists even after the drug treatment is discontinued (J Am Soc Nephrol 12: 659-666, 2001; Nephron 91: 710-718, 2002; Hypertens Res 30: 63-75, 2007). These results have been shown to be clinically relevant by the recent TROPHY study (N Engl J Med 354: 1685-1697, 2006). We have recently found that transient treatment with an ARB may also cause regression of established hypertension in hypertensive rats (J Am Soc Nephrol 18: 157A, 2007). The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) study is a prospective, randomized, open, blinded end-point study in patients aged 30-59 with a positive family history of hypertension that will be conducted in several centers in Japan. The aim of the study is to evaluate the antihypertensive drug withdrawal success rate, the median duration of drug withdrawal, and the changes in home and office blood pressure values in patients with mild hypertension after tapering and withdrawal of antihypertensive treatment following treatment for 1 year with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. A unique feature of this study is the use of a home blood pressure monitoring telemedicine system (i-TECHO) to allow frequent evaluation of the changes in blood pressure in the trial patients. This study will be the first clinical study to examine if regression from stage 1 (mild) hypertension to prehypertension (high-normal blood pressure) is possible using an ARB or CCB.

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Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats

Takimoto, C., Kumagai, H., Osaka, M., Sakata, K., Onami, T., Kamayachi, T., Iigaya, K., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 （ 10 ） 1941 - 51 2008年10月

ISSN  0916-9636

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The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

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Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice

Oyamada, N., Itoh, H., Sone, M., Yamahara, K., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

J Transl Med 6   54 2008年09月

ISSN  1479-5876

　概要を見る

BACKGROUND: We previously demonstrated that vascular endothelial growth factor receptor type 2 (VEGF-R2)-positive cells induced from mouse embryonic stem (ES) cells can differentiate into both endothelial cells (ECs) and mural cells (MCs) and these vascular cells construct blood vessel structures in vitro. Recently, we have also established a method for the large-scale expansion of ECs and MCs derived from human ES cells. We examined the potential of vascular cells derived from human ES cells to contribute to vascular regeneration and to provide therapeutic benefit for the ischemic brain. METHODS: Phosphate buffered saline, human peripheral blood mononuclear cells (hMNCs), ECs-, MCs-, or the mixture of ECs and MCs derived from human ES cells were intra-arterially transplanted into mice after transient middle cerebral artery occlusion (MCAo). RESULTS: Transplanted ECs were successfully incorporated into host capillaries and MCs were distributed in the areas surrounding endothelial tubes. The cerebral blood flow and the vascular density in the ischemic striatum on day 28 after MCAo had significantly improved in ECs-, MCs- and ECs+MCs-transplanted mice compared to that of mice injected with saline or transplanted with hMNCs. Moreover, compared to saline-injected or hMNC-transplanted mice, significant reduction of the infarct volume and of apoptosis as well as acceleration of neurological recovery were observed on day 28 after MCAo in the cell mixture-transplanted mice. CONCLUSION: Transplantation of ECs and MCs derived from undifferentiated human ES cells have a potential to contribute to therapeutic vascular regeneration and consequently reduction of infarct area after stroke.

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Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice

Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Nishiyama, A. and Itoh, H.

J Am Soc Hypertens 2 （ 5 ） 332 - 40 2008年09月

ISSN  1933-1711

　概要を見る

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.

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The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia

Oyamada, N., Sone, M., Miyashita, K., Park, K., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N., Itoh, H. and Nakao, K.

Endocrinology 149 （ 8 ） 3764 - 77 2008年08月

ISSN  0013-7227

　概要を見る

Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.

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Monosynaptic excitatory connection from the rostral ventrolateral medulla to sympathetic preganglionic neurons revealed by simultaneous recordings

Oshima, N., Kumagai, H., Onimaru, H., Kawai, A., Pilowsky, P. M., Iigaya, K., Takimoto, C., Hayashi, K., Saruta, T. and Itoh, H.

Hypertens Res 31 （ 7 ） 1445 - 54 2008年07月

ISSN  0916-9636

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To directly investigate whether a monosynaptic connection exists between neurons in the rostral ventrolateral medulla (RVLM) and sympathetic preganglionic neurons (SPNs), we used simultaneous extracellular recordings of RVLM neurons and whole-cell patch-clamp recordings of SPNs at the Th2 level and analyzed them by spike-triggered averaging. We averaged 200 sweeps of membrane potentials in SPN triggered by the spikes in the RVLM neuron. No clear postsynaptic potentials were detected in the averaged wave of SPNs before angiotensin II (Ang II) superfusion, whereas during superfusion with Ang II (6 micromol/L) on the medulla oblongata side alone excitatory postsynaptic potentials (EPSPs) were clearly found in the SPN of 3 out of 10 pairs at 40 +/- 1 ms after the averaged triggering spike in the RVLM neuron. We consider them to be monosynaptic EPSPs, because 1) the averaged EPSPs exhibited a sharp rise time, 2) the onset latency of the averaged EPSPs in the SPNs after the trigger spike in the RVLM was the same as the latency of the antidromic action potentials in the RVLM neurons in response to electrical stimulation of the SPNs, and 3) the amplitude of the averaged EPSPs was over 2 mV. In summary, combining simultaneous recording and spike-triggered averaging allowed us to demonstrate a monosynaptic excitatory connection between a single RVLM neuron and a single SPN in the thoracic spinal cord. Such connections provide the basis for the maintenance of sympathetic tone and the integrative reflex that relays through the RVLM. The results explain the mechanism by which Ang II in the RVLM area increases peripheral sympathetic activity and blood pressure.

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Pathologic roles of prorenin and (pro)renin receptor in the eye

Satofuka, S., Ichihara, A., Nagai, N., Tsubota, K., Itoh, H. and Ishida, S.

Front Biosci 13   3884 - 95 2008年05月

ISSN  1093-9946

　概要を見る

Recent reports indicated that tissue renin-angiotensin system (RAS) was upregulated and angiotensin II type 1 receptor signaling plays crucial roles in ocular inflammation and neovascularization; however, the precise mechanism for activating tissue RAS had not been defined until recently. (Pro)renin receptor, a recently identified molecule existing in the major organs but not in the circulation, has attracted growing attention as an activator of tissue RAS. When the handle region of the prorenin prosegment binds to (pro)renin receptor, prorenin undergoes a conformational change to its enzymatically active state without the conventional proteolysis of the prorenin prosegment. Systemic treatment with a peptide with the structure of the handle region (handle region peptide; HRP), which competitively binds to (pro)renin receptor as a decoy peptide and inhibit the nonproteolytic activation of prorenin, resulted in the suppression of retinal inflammation and neovascularizaion in the rodent models. Retinal expression of RAS-related inflammatory and angiogenic molecules, such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, and vascular endothelial growth factor, was also suppressed with application of HRP. These findings demonstrate that nonproteolytically activated prorenin plays a significant role in the ocular inflammation and neovascularization.

Augmentation of neovascularization [corrected] in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells

Yamahara, K., Sone, M., Itoh, H., Yamashita, J. K., Yurugi-Kobayashi, T., Homma, K., Chao, T. H., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Fukunaga, Y., Tamura, N. and Nakao, K.

PLoS One 3 （ 2 ） e1666 2008年02月

ISSN  1932-6203

　概要を見る

BACKGROUND: We demonstrated that mouse embryonic stem (ES) cells-derived vascular endothelial growth factor receptor-2 (VEGF-R2) positive cells could differentiate into both endothelial cells (EC) and mural cells (MC), and termed them as vascular progenitor cells (VPC). Recently, we have established a method to expand monkey and human ES cells-derived VPC with the proper differentiation stage in a large quantity. Here we investigated the therapeutic potential of human VPC-derived EC and MC for vascular regeneration. METHODS AND RESULTS: After the expansion of human VPC-derived vascular cells, we transplanted these cells to nude mice with hindlimb ischemia. The blood flow recovery and capillary density in ischemic hindlimbs were significantly improved in human VPC-derived EC-transplanted mice, compared to human peripheral and umbilical cord blood-derived endothelial progenitor cells (pEPC and uEPC) transplanted mice. The combined transplantation of human VPC-derived EC and MC synergistically improved blood flow of ischemic hindlimbs remarkably, compared to the single cell transplantations. Transplanted VPC-derived vascular cells were effectively incorporated into host circulating vessels as EC and MC to maintain long-term vascular integrity. CONCLUSIONS: Our findings suggest that the combined transplantation of human ES cells-derived EC and MC can be used as a new promising strategy for therapeutic vascular regeneration in patients with tissue ischemia.

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Therapeutic potential of atrial natriuretic peptide administration on peripheral arterial diseases

Park, K., Itoh, H., Yamahara, K., Sone, M., Miyashita, K., Oyamada, N., Sawada, N., Taura, D., Inuzuka, M., Sonoyama, T., Tsujimoto, H., Fukunaga, Y., Tamura, N. and Nakao, K.

Endocrinology 149 （ 2 ） 483 - 91 2008年02月

ISSN  0013-7227

　概要を見る

Peripheral arterial diseases are caused by arterial sclerosis and impaired collateral vessel formation, which are exacerbated by diabetes, often leading to leg amputation. We have reported that an activation of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway accelerated vascular regeneration and blood flow recovery in murine legs, for which ischemia had been induced by a femoral arterial ligation as a model for peripheral arterial diseases. In this study, ip injection of carperitide, a human recombinant atrial natriuretic peptide, accelerated blood flow recovery with increasing capillary density in ischemic legs not only in nondiabetic mice but also in mice kept upon streptozotocin-induced hyperglycemia for 16 wk, which significantly impaired the blood flow recovery compared with nondiabetic mice. Based on these findings, we tried to apply the administration of carperitide to the treatment of peripheral arterial diseases. The study group comprised a continuous series of 13 patients with peripheral arterial diseases (Fontaine's classification I, one; II, five; III, two; and IV, five), for whom conventional therapies had not accomplished appreciable results. Carperitide was administrated continuously and intravenously for 2 wk to Fontaine's class I-III patients and for 4 weeks to class IV patients. The dose was gradually increased to the maximum, with the patient's systolic blood pressure being kept above 100 mm Hg. Carperitide administration improved the ankle-brachial pressure index, intermittent claudication, rest pain, and ulcers. In conclusion, this study showed a therapeutic potential of carperitide to treat peripheral arterial diseases refractory to conventional therapies.

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Effects of pretreatment with low-dose metformin on metabolic parameters and weight gain by pioglitazone in Japanese patients with type 2 diabetes

Kawai, T., Funae, O., Shimada, A., Tabata, M., Hirata, T., Atsumi, Y. and Itoh, H.

Intern Med 47 （ 13 ） 1181 - 8 2008年

ISSN  0918-2918

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OBJECTIVE: We investigated whether or not "low dose" metformin could prevent weight gain induced by pioglitazone. RESEARCH DESIGN AND METHODS: Sixty-nine patients with type 2 diabetes received 500-750 mg metformin a day for 12 weeks as an observation period before the start of the intervention. After an observation period, inadequately controlled patients (hemoglobin A1c >or=7.5%, n=34) received additional treatment with 15 mg pioglitazone (+P, M+P group). The other patients (n= 35) continued metformin monotherapy (Met group). In addition, another group consisting of 28 patients treated with 15 mg pioglitazone alone (Pio group) was observed. Body mass index (BMI), as well as several clinical parameters of glycemic control and lipid metabolism, was compared before and after 24 weeks of intervention. RESULTS: BMI increased significantly in the Pio group [24.0+/-3.8 vs. 24.8+/-4.3 kg/m(2), (mean +/- SD), p<0.001], but not in the M+P group (25.1+/-3.5 vs. 25.3+/-3.4 kg/m(2), NS) and Met group (24.0+/-3.3 vs. 24.0+/-3.5 kg/m(2), NS). In addition to improvement in glycemic control, a significant reduction in the atherogenic index of plasma (AIP), defined as log [TG x0.0112/HDL-C x0.02586], was observed in the Pio group (0.06+/-0.23 vs. -0.04+/-0.27, p<0.05) and M+P group (0.08+/-0.24 vs. -0.001+/-0.252, p<0.01), but not in the Met group. CONCLUSION: This study indicates potential benefits of the addition of pioglitazone to "low dose" metformin in terms of improvement of glucose and lipid metabolism without weight gain.

Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration

Sone, M., Itoh, H., Yamahara, K., Yamashita, J. K., Yurugi-Kobayashi, T., Nonoguchi, A., Suzuki, Y., Chao, T. H., Sawada, N., Fukunaga, Y., Miyashita, K., Park, K., Oyamada, N., Sawada, N., Taura, D., Tamura, N., Kondo, Y., Nito, S., Suemori, H., Nakatsuji, N., Nishikawa, S. and Nakao, K.

Arterioscler Thromb Vasc Biol 27 （ 10 ） 2127 - 34 2007年10月

ISSN  1079-5642

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OBJECTIVE: We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration. METHODS AND RESULTS: Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60-negative cells were also positive for platelet-derived growth factor receptor alpha and beta chains and could be effectively differentiated into both VE-cadherin+ endothelial cell and alpha-smooth muscle actin+ mural cell. VE-cadherin+ cells, which were also CD34+ and VEGF-R2+ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow. CONCLUSIONS: We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

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心血管事故の元、動脈硬化は食い止められるか

伊藤裕

まいんど 19 （ 8月 ） 39702 2007年08月

研究論文（学術雑誌）, 単著