Synergistic interactions of hypertension and diabetes in promoting kidney injury

项目总结/摘要 在过去的几十年中，糖尿病在美国急剧增加，并迅速增加。 成为我们医疗体系的一大挑战。许多糖尿病患者也患有高血压（HT）， 这显著增加了糖尿病肾病进展为终末期肾病的风险 （ESRD）。临床和实验研究表明，抗高血压治疗只能减缓进展 因此，迫切需要揭示其机制， 负责糖尿病-HT肾病，并确定新的治疗靶点。II型糖尿病的初步研究 糖尿病动物模型表明，即使是适度的血压增加，当叠加在中度 糖尿病，极大地增强了肾损伤，如通过显著增加的蛋白尿和快速下降， GFR。此外，抑制内质网（ER）应激和清除活性氧 (ROS)线粒体（MT）的内质网应激和MT功能障碍对肾脏有保护作用， 可能是HT与糖尿病协同作用的关键因素。也有证据表明 机械敏感性瞬时受体电位阳离子通道，亚家族C，成员6（TRPC 6）可能具有 在糖尿病肾病肾小球损伤的发展中起重要作用。因此，它假设 在II型糖尿病中HT和糖尿病的共存协同放大了氧化应激和细胞凋亡， 足细胞和肾小球内皮损伤。这种协同效应是由HT诱导的机械 拉伸激活TRPC通道，并通过ER应激、线粒体 功能障碍和受损的Ca 2+稳态。在指导阶段，分子机制， 将确定由高血压引起的机械力与糖尿病相互作用以促进肾损伤 使用体外和体内模型。HT和糖尿病对ER应激分子途径的协同作用， 肾小球毛细血管内皮细胞和足细胞中的线粒体功能障碍和TRPC 6活化将是 也评价。在独立阶段，TRPC 6缺乏对糖尿病患者的肾脏保护作用是不明显的。 HT肾损伤将使用新的基因工程动物模型进行检查。本研究结果 将提供TRPC 6通道在介导糖尿病-HT肾病中的作用的新信息。总的来说， 该项目将促进申请人的持续技术，智力和专业培训，并将协助 申请人在学术研究机构建立独立的研究实验室。

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.