Renin activation in early diabetes

描述（由申请人提供）：糖尿病和肥胖症的发病率在美国和世界范围内迅速上升至流行水平。高血压是糖尿病的代谢标志，是糖尿病并发症的重要致病因素，导致数百万美国人的显著发病率和死亡率。高血压与许多器官（包括肾脏）的微血管并发症明显相关，糖尿病肾病是发达国家终末期肾病（ESRD）的主要原因。此外，糖尿病可导致大血管并发症和全身性高血压。高血糖症的细胞和肾脏特异性效应的最新进展将局部肾内肾素-血管紧张素系统（RAS）的激活作为导致其他生化和细胞缺陷以及由此产生的肾组织损伤的核心异常的强有力候选者。肾小球细胞释放的肾素是RAS激活的限速步骤。新发现的G-蛋白偶联受体GPR 91，由柠檬酸循环中间体琥珀酸激活，可能提供葡萄糖代谢和血压的肾素依赖性增加之间的联系。我们最近建立了一种成像技术，可以直接在完整的活体肾脏组织中观察到肾素含量、释放和组织活性。本申请的广泛、长期目标是确定早期糖尿病中的高血糖症引起新鉴定的肾特异性代谢受体GPR 91的活化，其继而启动旁分泌信号传导并触发肾素释放和肾小球超滤。该基金的具体目标是鉴定参与琥珀酸信号传导的细胞类型和分子，建立体外高糖诱导的肾素释放机制，并测试GPR 91/肾素在体内糖尿病并发症发展中的重要性。原代细胞培养物、分离的体外微灌注传入小动脉-肾小球制备物以及体内小鼠和大鼠肾脏动物模型将与多光子荧光显微镜和实时成像结合使用。这些研究应该产生临床重要信息，可用于开发新药和治疗方法，以更好地治疗糖尿病肾脏并发症以及高血压。

DESCRIPTION (provided by applicant): The incidence of diabetes mellitus and obesity are rapidly rising to epidemic levels in the United States and worldwide. Hyperglycemia, the metabolic hallmark of diabetes is a significant causative factor for the complications of diabetes mellitus, which results in significant morbidity and mortality for millions of Americans. Hyperglycemia is clearly associated with microvascular complications in many organs including the kidney, and diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in developed countries. In addition, diabetes may lead to macrovascular complications and systemic hypertension. Recent advances on the cellular and kidney-specific effects of hyperglycemia places the activation of the local, intra-renal renin-angiotensin system (RAS) as a strong candidate for the core abnormality that leads to other biochemical and cellular defects and the resulting renal tissue injury. Renin release from juxtaglomerular cells is the rate-limiting step of RAS activation. Novel discovery of the G-protein-coupled receptor GPR91, activated by citric acid cycle intermediate succinate, may provide a link between glucose metabolism and renin-dependent increases in blood pressure. We have recently established an imaging technique in which renin content, release, and tissue activity can be directly visualized in the intact living kidney tissue. The broad, long-term objective of this application is to establish that hyperglycemia in early diabetes causes the activation of the newly identified, kidney-specific metabolic receptor GPR91 which in turn initiates paracrine signaling and triggers renin release and glomerular hyperfiltration. Specific aims of this grant are to identify the cell types and molecules involved in succinate signaling, establish the mechanism of high glucose-induced renin release in vitro, and test the importance of GPR91/renin in the development of diabetic complications in vivo. Primary cell cultures, the isolated, in vitro microperfused afferent arteriole-glomerulus preparation, and in vivo mouse and rat kidney animal models will be used in combination with multi-photon fluorescence microscopy, and real-time imaging. These studies should yield clinically important information that can be used to develop new drugs and therapeutic approaches for the better treatment of diabetic complications in the kidney as well as high blood pressure.