Pathobiology of HMG-CoA reductase inhibitors in diabetes

HMG-CoA 还原酶抑制剂在糖尿病中的病理学

• 批准号: 6707485
• 负责人: Yashpal S. Kanwar
• 金额: $ 32.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6707485
• 关键词: ACE inhibitors; G protein; HMG coA reductases; NAD(P)H dehydrogenase; NOD mouse; angiotensin II; biological signal transduction; cyclin dependent kinase; diabetic nephropathy; enzyme inhibitors; enzyme linked immunosorbent assay; extracellular matrix; flow cytometry; guanosinetriphosphatases; laboratory rat; northern blottings; simvastatin; tissue /cell culture; transfection; ventricular hypertrophy; western blottings

DESCRIPTION (provided by applicant): Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also known as statins, are widely used lipid-lowering agents in prevention of coronary heart disease. Recent experimental and clinical data, however, indicate that the overall benefits of statin therapy may exceed its cholesterollowering properties. For instance, it has been recently shown that statins modulate glucose-induced mesangial cells (MC) proliferation via small GTPase proteins (Danesh et. al., ref. # 18, appendix # 1). In this proposal, we hypothesize that statins may ameliorate the detrimental effects of angiotensin (Ang) II-induced MC hypertrophy, a hallmark of diabetic nephropathy, by preventing Rho GTPase isoprenylation. We therefore propose to examine the modulatory effects of simvastatin, a hydrophobic HMG-CoA reductase inhibitor, on a novel signaling pathway activated by Ang II. To determine whether the renoprotective effect of simvastatin will translate into a significant improvement in reducing albuminuria in vivo, studies are proposed using NOD mice and streptozotocin-induced diabetic rats, established models of type 1 diabetes. Specifically, we will address the following questions: I. What is the role of Rho family of small GTPases in Ang II-induced MC hypertrophy and extracellular matrix expansion, and how does simvastatin modulate the activation of Rho family of small GTPases? II. What is the role of membrane-bound NAD(P)H oxidase, a recently discovered oxidative stress signaling pathway in Ang II-induced MC hypertrophy, and does simvastatin interfere with this signaling pathway? III. Are CIP/KIP family of cyclin dependent kinase inhibitors involved in Rho GTPase-regulated Ang II-induced MC hypertrophy? and IV. What are the renoprotective effects of simvastatin on two established models of type 1diabetes, NOD mouse and in rats with streptozotocin-induced diabetes? The findings of this proposal should not only give impetus for future studies to investigate the effects of statins in the prevention and treatment of nephropathy in diabetic patients, but will also provide insights into a novel Ang II-induced Rac1-regulated, membrane-bound NAD(P)H-dependent oxidase ,signaling pathway involving Akt/PKB kinase and CDK-inhibitors in MC hypertrophy.

描述（由申请人提供）：3-羟基-3-甲基戊二酰辅酶A（HMG-COA）还原酶的抑制剂，也称为他汀类药物，是预防冠状心脏疾病的广泛使用的降低脂质剂。但是，最近的实验和临床数据表明，他汀类药物治疗的总体益处可能超过其胆固醇的特性。例如，最近已经表明，他汀类药物通过小的GTPase蛋白调节葡萄糖诱导的肾小球细胞（MC）增殖（Danesh等，参考文献＃18，附录＃1）。在该提案中，我们假设他汀类药物可以通过防止Rho GTPase异丙肾上腺素化来缓解血管紧张素（ANG）II诱导的MC肥大的有害作用，这是糖尿病性肾病的标志。因此，我们建议检查辛伐他汀（一种疏水性HMG-COA还原酶抑制剂）对ANG II激活的新信号传导途径的调节作用。为了确定辛伐他汀的肾脏保护作用是否会转化为减少体内蛋白尿的显着改善，使用NOD小鼠和链蛋白酶诱导的糖尿病大鼠提出了研究，这是1型糖尿病的建立模型。具体而言，我们将解决以下问题：I。小gtpases在ANG II引起的MC肥大和细胞外基质扩张中的作用是什么？辛伐他汀如何调节小GTPases的Rho家族的激活？ ii。膜结合的NAD（P）H氧化酶的作用是什么，ANG II诱导的MC肥大中最近发现的氧化应激信号通路，辛伐他汀是否会干扰这种信号传导途径？ iii。 CIP/KIP家族是否参与RHO GTPase调节的ANG II诱导的MC肥大的CIP/KIP家族？和IV。辛伐他汀对两种型糖尿病类型的既定模型，点头小鼠以及链蛋白酶诱导的糖尿病的大鼠的肾脏保护作用是什么？该提案的发现不仅应为未来的研究提供动力，以调查他汀类药物在糖尿病患者中预防和治疗肾病中的影响，而且还将提供有关一种新型ANG II ANG II诱导的，膜结合的NAD NAD（P）H依赖性氧化酶，涉及AKT/PKBKINPOPASE的新型ANG II诱导的NAD NAD（P）HAD诱导的NAD NAD（P）HARTISN和CDK KINID和CDKINID和CDKINIFF cDKINDING和CDKINRING cDKINID。