Renin activation in early diabetes

早期糖尿病中的肾素激活

• 批准号: 7318531
• 负责人: JANOS PETI-PETERDI
• 金额: $ 24.45万
• 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/7318531
• 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）：糖尿病和肥胖症的发生率迅速上升到美国和全球的流行水平。高血糖，糖尿病的代谢标志是糖尿病并发症的重要病因，这导致了数百万美国人的显着发病率和死亡率。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，糖尿病性肾病是发达国家终末期肾脏疾病（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。高血糖的细胞和肾脏特异性作用的最新进展使局部肾上腺内血管紧张素系统（RAS）的激活是导致其他生物化学和细胞缺陷的核心异常的强大候选者，并导致了肾脏组织损伤。肾素释放从并置细胞释放是RAS激活的速率限制步骤。由柠檬酸循环中间琥珀酸酯激活的G蛋白偶联受体GPR91的新发现，可能会提供葡萄糖代谢与肾素依赖性升高之间的联系。我们最近建立了一种成像技术，其中肾素含量，释放和组织活性可以直接在完整的活肾组织中可视化。该应用的广泛长期目标是确定早期糖尿病的高血糖会导致新鉴定的肾脏特异性代谢受体GPR91的激活，这又启动了旁分泌信号传导，并触发肾素释放和肾小球过滤。该赠款的具体目的是确定琥珀酸信号传导所涉及的细胞类型和分子，在体外建立高葡萄糖诱导的肾素释放的机制，并测试GPR91/肾素在体内发展糖尿病并发症中的重要性。原代细胞培养物，分离的，体外的微型融合的传入动脉 - 胶质膜制剂，体内小鼠和大鼠肾动物模型将与多光子荧光显微镜和实时成像结合使用。这些研究应产生临床上重要的信息，这些信息可用于开发新药和治疗方法，以更好地治疗肾脏和高血压。