Renin activation in early diabetes

描述（由申请人提供）：在美国和世界范围内，糖尿病和肥胖症的发病率正在迅速上升到流行病的水平。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，导致数百万美国人的发病率和死亡率很高。高血糖与包括肾脏在内的许多器官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，糖尿病可能导致大血管并发症和全身性高血压。最近关于高血糖的细胞和肾脏特异性效应的研究进展表明，局部肾内肾素-血管紧张素系统（RAS）的激活是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。肾素从肾小球旁细胞释放是RAS激活的限速步骤。新发现的g蛋白偶联受体GPR91，由柠檬酸循环中间琥珀酸激活，可能提供葡萄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观察肾素的含量、释放和组织活性。该应用的广泛和长期目标是确定早期糖尿病的高血糖引起新发现的肾脏特异性代谢受体GPR91的激活，从而启动旁分泌信号传导并触发肾素释放和肾小球高滤过。本资助的具体目的是确定参与琥珀酸盐信号传导的细胞类型和分子，建立高糖诱导肾素在体外释放的机制，并在体内测试GPR91/肾素在糖尿病并发症发生中的重要性。原代细胞培养、离体、体外微灌注传入小动脉-肾小球制备、小鼠和大鼠体内肾脏动物模型将结合多光子荧光显微镜和实时成像技术进行研究。这些研究将产生重要的临床信息，可用于开发新的药物和治疗方法，以更好地治疗肾脏和高血压的糖尿病并发症。

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.