Synergistic interactions of hypertension and diabetes in promoting kidney injury

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Diabetes mellitus has increased dramatically in the U.S. during the last several decades and has rapidly become a major challenge to our healthcare system. Many patients with diabetes are also hypertensive (HT), which substantially increases the risk for progression of diabetic nephropathy to end-stage renal disease (ESRD). Clinical and experimental studies indicate that antihypertensive treatment only slows the progression of nephropathy to ESRD rather than halting it. Therefore, there is an urgent need to reveal the mechanisms responsible for diabetic-HT nephropathy and to identify new therapeutic targets. Preliminary studies in a type II diabetic animal model indicate that even a moderate increase in BP, when superimposed on moderate diabetes, greatly enhances renal injury as reflected by significantly increased proteinuria and rapid decline in GFR. In addition, inhibition of endoplasmic reticulum (ER) stress and scavenging of reactive oxygen species (ROS) from mitochondria (MT) have renal protective effects, suggesting that ER stress and MT dysfunction may be key factors in contributing to the synergistic effects of HT plus diabetes. There is also evidence that mechanically sensitive transient receptor potential cation channels, subfamily C, member 6 (TRPC6) may have an important role in the development of glomerular injury in diabetic nephropathy. Therefore, it hypothesizes that coexistence of HT and diabetes in type II diabetes synergistically amplifies oxidative stress and cellular injury in podocytes and endothelium of glomeruli. This synergistic effect is mediated by HT-induced mechanical stretch which activates TRPC channels and is amplified by the interaction of ER stress, mitochondrial dysfunction and impaired Ca2+ homeostasis. During the mentored phase, the molecular mechanisms by which mechanical forces induced by hypertension interact with diabetes to promote renal injury will be determined using in vitro and in vivo models. Synergistic effects of HT and diabetes on molecular pathways of ER stress, mitochondrial dysfunction and TRPC6 activation in glomerular capillary endothelial cells and podocytes will be evaluated as well. During the independent phase, the renal protective effect of TRPC6 deficiency in diabetic- HT kidney injury will be examined using novel genetically engineered animal models. Results from this study will provide novel information on the role of TRPC6 channels in mediating diabetic-HT nephropathy. Overall, this project will facilitate applicant's continued technical, intellectual, and professional training, and will assist the applicant in establishing an independent research laboratory at an academic research institution.