Pathobiology of HMG-CoA reductase inhibitors in diabetes

描述（由申请人提供）：3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶抑制剂，也称为他汀类药物，是广泛用于预防冠心病的降脂药物。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胆固醇的特性。例如，最近有研究表明，他汀类药物通过小GTPase蛋白调节葡萄糖诱导的肾小球系膜细胞（MC）增殖（Danesh et. al., ref. # 18，附录# 1）。在这项提议中，我们假设他汀类药物可以通过阻止Rho GTPase异戊二烯化来改善血管紧张素（Ang） ii诱导的MC肥大（糖尿病肾病的标志）的有害影响。因此，我们建议研究辛伐他汀（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保护作用是否会转化为体内减少蛋白尿的显著改善，我们提出了使用NOD小鼠和链脲佐菌素诱导的糖尿病大鼠进行研究，这是建立的1型糖尿病模型。具体而言，我们将解决以下问题：1 .小GTPases的Rho家族在Ang ii诱导的MC肥大和细胞外基质扩张中的作用，辛伐他汀如何调节小GTPases的Rho家族的激活？2。新近发现的氧化应激信号通路——膜结合NAD(P)H氧化酶在Ang ii诱导的MC肥大中的作用是什么？辛伐他汀是否会干扰这一信号通路？3。细胞周期蛋白依赖性激酶抑制剂CIP/KIP家族是否参与Rho gtpase调控的angii诱导的MC肥大？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）的肾保护作用是什么？该研究结果不仅将推动未来研究他汀类药物在糖尿病患者肾病预防和治疗中的作用，而且还将为研究一种新的Ang ii诱导的rac1调节的、膜结合的NAD(P) h依赖性氧化酶、涉及Akt/PKB激酶和cdk抑制剂的MC肥大信号通路提供新的见解。

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.