New therapeutic strategy for diabetic complications targeting NAD(P)H oxidase activation mechanism
| Project/Area Number |
16590888
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kyushu University |
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Principal Investigator |
INOGUCHI Toyoshi Kyushu University, Hospital, Assistant Professor, 大学病院, 講師 (00294926)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Kunihisa Kyushu University, Graduate School of Medical Sciences, Research Associate, 大学院医学研究院, 助手 (30335963)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | Diabetes / vascular complications / pancreatic beta cell / oxidative stress / NAD / H oxidase / protein kinase C / renin-angiotensin / 糖毒性 / レニンアンギオテンシン系 / NAD(P)Hオキシターゼ |
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| Research Abstract |
In this study, we revealed that NAD(P)H oxidase activation may be a major source for increased oxidative stress in diabetic vascular tissues, and that such NAD(P)H oxidase activation may be mediated by high glucose and activation of local renin-angiotensin system (RAS).
In animal models of type 2 diabetes, NAD(P)H oxidase-generated reactive oxygen species (ROS) was increased in islets as well as vascular tissues and this was normalized by angitensin II type 2 receptor blocker, suggesting the role of local RAS activation. To explore the mechanism for local RAS activation, we examined the expression of chymase, an important angiotensin-converting enzyme in local tissues. The expression of chymase was significantly increased in renal tissues, cardiovascular tissues and islets of type 2 diabetic animal models. Taken together, these results suggested that both high glucose and increased expression of chymase-induced NAD(P)H oxidase may play an important role in the pathogenesis of both vascu
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lar complications and beta cell damage in diabetes.
We examined whether targeting these mechanisms really normalize vascular complications. We found that statin normalized the incresaed expression of NOX4,a major component of NAD(P)H oxidase in diabetic kidney and subsequently normalized proteinuria and mesangial expansion in diabetic rats. Next, we also found that bilirubin has a capability of inhibiting NAD(P)H oxidase. In this context, we performed the epidemiological study and evaluated the prevalence of vascular complications in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia. The prevalence of retinopathy, nephropathy and cardiovascular disease was remarkably reduced in diabetic patients with Gilbert syndrome as compared with those without it. These findings suggested that hyperbilirubinemia may inhibit the development of diabetic vascular complications via inhibition of NAD(P)H oxidase. We are now trying to develop new therapeutic agents for inhibiting vascular complication along these lines. Less
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Report
(4 results)
Research Products
(59 results)
