Pathobiology of HMG-CoA reductase inhibitors in diabetes

性状（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。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特性。例如，最近已经显示他汀类药物通过小GT3蛋白调节葡萄糖诱导的肾小球系膜细胞（MC）增殖（Danesh et.例如，参考文献#18，附录#1）。在这个建议中，我们假设他汀类药物可能会改善血管紧张素（Ang）II诱导的MC肥大的不利影响，糖尿病肾病的标志，通过阻止Rho GT3异戊二烯化。因此，我们建议研究辛伐他汀，疏水性HMG-CoA还原酶抑制剂，对血管紧张素II激活的一种新的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减少体内白蛋白尿的显著改善，提出了使用NOD小鼠和链脲佐菌素诱导的糖尿病大鼠（建立的1型糖尿病模型）进行研究。具体而言，我们将讨论以下问题：一。Rho家族的小GTP酶在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家族的小GTP酶的激活？二.膜结合NAD（P）H氧化酶是一种新近发现的氧化应激信号通路，它在Ang II诱导的MC肥大中起什么作用？辛伐他汀是否会干扰这一信号通路？三.细胞周期蛋白依赖性激酶抑制剂CIP/KIP家族是否参与Rho GTP酶调节Ang II诱导的MC肥大？和IV.辛伐他汀对2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脏保护作用是什么？这一发现不仅将为进一步研究他汀类药物预防和治疗糖尿病肾病的作用提供动力，而且还将为了解一种新的Ang II诱导的Rac 1调节的膜结合NAD（P）H依赖性氧化酶、涉及Akt/PKB激酶的信号通路和MC肥大中的CDK抑制剂提供见解。

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.