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: 6855801
• 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/6855801
• 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（申请人提供）：3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，也称为他汀类药物，是广泛用于预防冠心病的降脂剂。然而，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降低胆固醇的特性。例如，最近发现他汀类药物通过小 GTP 酶蛋白调节葡萄糖诱导的系膜细胞 (MC) 增殖（Danesh 等人，参考文献 # 18，附录 # 1）。在这项提议中，我们假设他汀类药物可能通过阻止 Rho GTP 酶异戊二烯化来改善血管紧张素 (Ang) II 诱导的 MC 肥大（糖尿病肾病的一个标志）的有害影响。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 激活的新型信号通路的调节作用。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白蛋白尿的显着改善，建议使用 NOD 小鼠和链脲佐菌素诱导的糖尿病大鼠进行研究，建立 1 型糖尿病模型。具体来说，我们将解决以下问题：一、Rho小GTP酶家族在Ang II诱导的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Rho小GTP酶家族的激活？二.膜结合 NAD(P)H 氧化酶是最近发现的一种氧化应激信号通路，在 Ang II 诱导的 MC 肥大中起什么作用？辛伐他汀是否会干扰该信号通路？三． CIP/KIP 细胞周期蛋白依赖性激酶抑制剂家族是否参与 Rho GTPase 调节的 Ang II 诱导的 MC 肥大？和四。辛伐他汀对两种已建立的 1 型糖尿病模型（NOD 小鼠）和链脲佐菌素诱导的糖尿病大鼠有什么肾脏保护作用？该提案的结果不仅会推动未来研究他汀类药物在预防和治疗糖尿病患者肾病中的作用，而且还将为新型 Ang II 诱导的 Rac1 调节的膜结合 NAD 提供见解(P)H 依赖性氧化酶、信号通路涉及 MC 肥大中的 Akt/PKB 激酶和 CDK 抑制剂。