Renin activation in early diabetes

描述(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到流行水平。高血糖是糖尿病的代谢标志，是糖尿病并发症的重要致病因素，糖尿病并发症导致数百万美国人的严重发病率和死亡率。高血糖明显与包括肾脏在内的许多器官的微血管并发症有关，在发达国家，糖尿病肾病是终末期肾病(ESRD)的主要原因。此外，糖尿病还可能导致大血管并发症和系统性高血压。高血糖的细胞和肾脏特异性效应的最新进展使局部肾素-血管紧张素系统(RAS)的激活成为导致其他生化和细胞缺陷以及由此导致的肾组织损伤的核心异常的有力候选者。肾素从肾小球旁细胞释放是RAS激活的限速步骤。由柠檬酸循环中间体琥珀酸激活的G蛋白偶联受体GPR91的新发现可能提供了糖代谢和肾素依赖性血压升高之间的联系。我们最近建立了一种成像技术，可以在完整的活肾组织中直接显示肾素的含量、释放和组织活动。这项应用的广泛和长期目标是确定早期糖尿病的高血糖导致新发现的肾脏特异性代谢受体GPR91的激活，GPR91进而启动旁分泌信号并触发肾素释放和肾小球高滤过。这项资助的具体目的是鉴定参与琥珀酸信号转导的细胞类型和分子，建立体外高糖诱导肾素释放的机制，并测试GPR91/肾素在体内糖尿病并发症发展中的重要性。原代细胞培养、分离的、体外微灌流的传入小动脉-肾小球准备，以及活体小鼠和大鼠肾脏动物模型将结合多光子荧光显微镜和实时成像。这些研究应该产生临床上重要的信息，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和高血压。

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.