Pathobiology of HMG-CoA Reductase Inhibitors in Diabetes

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.