Renin activation in early diabetes

早期糖尿病中的肾素激活

• 批准号: 7460801
• 负责人: JANOS PETI-PETERDI
• 金额: $ 23.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460801
• 关键词: American; Angiotensinogen; Animal Model; Biochemical; Biosensor; Blood Pressure; Blood Vessels; Calcium; Cells; Citric Acid Cycle; Complex; Complications of Diabetes Mellitus; Data; Defect; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Dinoprostone; End stage renal failure; Endothelial Cells; Epidemic; Event; Experimental Models; Feedback; Figs - dietary; Fluorescence Microscopy; G-Protein-Coupled Receptors; Glucose; Grant; High Blood Pressure; Hyperglycemia; Hypertension; Image; Imaging Techniques; Immunohistochemistry; In Vitro; Incidence; Injury; Juxtaglomerular Cell; Kidney; Knockout Mice; Lead; Life; Link; Mediating; Metabolic; Modeling; Morbidity - disease rate; Mus; Nitric Oxide; Obesity; Organ; Paracrine Communication; Pharmaceutical Preparations; Preparation; Primary Cell Cultures; Prostaglandin Production; Range; Rate; Rattus; Receptor Activation; Renal Tissue; Renin; Renin-Angiotensin System; Research Personnel; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Succinates; Techniques; Testing; Text; Therapeutic; Time; Tissues; United States; Vascular Endothelium; Vasodilation; Work; arteriole; base; cell type; diabetic; glucose metabolism; in vivo; inhibitor/antagonist; macrovascular disease; mortality; multi-photon; novel; paracrine; programs; receptor; succinate

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.

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至流行病水平。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，导致数百万美国人显着发病和死亡。高血糖显然与包括肾脏在内的许多器官的微血管并发症有关，而糖尿病肾病是发达国家终末期肾病（ESRD）的主要原因。此外，糖尿病还可能导致大血管并发症和全身性高血压。关于高血糖的细胞和肾脏特异性影响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的核心异常的有力候选者。受伤。肾素从肾小球旁细胞的释放是 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 的新发现可能提供葡萄糖代谢与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，可以直接观察完整的活肾组织中的肾素含量、释放和组织活性。该应用的广泛、长期目标是确定早期糖尿病中的高血糖会导致新发现的肾脏特异性代谢受体 GPR91 的激活，进而启动旁分泌信号传导并触发肾素释放和肾小球过度滤过。该资助的具体目的是鉴定参与琥珀酸信号传导的细胞类型和分子，建立体外高葡萄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。原代细胞培养物、分离的体外微灌注传入小动脉-肾小球制剂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。