Glomerular and Tubular Function in the Diabetic Kidney

糖尿病肾的肾小球和肾小管功能

• 批准号: 10170328
• 负责人: SCOTT Culver THOMSON
• 金额: $ 43.23万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170328
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Agonist; Antidiabetic Drugs; Blood Glucose; Blood Pressure; Caring; Clinical; Clinical Trials; Consumption; Coupling; Diabetes Mellitus; Diet; Electron Transport; Elements; Equilibrium; GLP-I receptor; Glomerular Capillary; Gluconeogenesis; Glucose; Goals; Growth; Homeostasis; Hypersensitivity; Hypertension; Hypoxia; Kidney; Knowledge; Logic; Measures; Mediating; Medical; Metabolic; Metabolic stress; Metabolism; Metformin; Methods; Micropuncture; Modeling; Mus; Nephrons; Organ; Outcome; Oxygen; Oxygen Consumption; Patients; Pharmaceutical Preparations; Physiology; Public Health; Rattus; Receptor Activation; Recommendation; Renal Blood Flow; Renal function; Research; Role; Series; Systems Theory; Testing; Time; Tissues; Tubular formation; Work; diabetic; diabetic patient; dietary; dietary salt; exenatide; experimental study; glomerular filtration; hemodynamics; in vivo; inhibitor/antagonist; insight; kidney fibrosis; mitochondrial dysfunction; pressure; protective effect; renal hypoxia; response; saluretic; treatment effect

PROJECT SUMMARY ABSTRACT The kidney is unique among the body organs in that it responds to early diabetes by growing large and increasing its function and oxygen consumption (QO2). We are drawn to understand this physiology because growth, hyperfunction, and low cortical PO2 in the early diabetic kidney predict subsequent damage and decline. For the past 15 years, we have characterized glomerular and tubular function in the early diabetic kidney with particular emphasis on how glomerular filtration and proximal reabsorption affect each other. This application is focused on the renal effects of dietary salt and of common drugs that are already in the armamentarium of diabetes care. These drugs include inhibitors of the Na-glucose cotransporter SGLT2 and agonists of the glucagon-like peptide 1 receptor (GLP-1R). SGLT2 inhibitors and GLP-1R agonists are being administered to millions of diabetic patients, and lowering of the dietary salt would apply to millions more if public health recommendations were successfully implemented. Each of these maneuvers has off-target effects on glomerular and tubular function, the nuances of which we intend to investigate. The goal is to facilitate the acquisition of medical knowledge by providing a basis in physiology for developing hypotheses that are worth bringing to clinical trials for renal protection and for providing a scientific explanation of the outcome of such trials that are already in progress. The experimental work is divided into 3 Specific Aims. Each aim addresses the impact of dietary salt, SGLT2 blockade, and GLP-1R activation on a particular aspect of kidney physiology. The three aspects of kidney physiology are 1) proximal tubular growth and transport, 2) renal hemodynamics, and 3) renal metabolism. A network assembled from cause-effect relations among transport, hemodynamic, and metabolic variables provides insight to the organic physiology that could not be determined by studying transport, hemodynamics, and metabolism in isolation.

项目摘要 肾脏在身体器官中是独特的，因为它对早期糖尿病的反应是变大， 增加其功能和耗氧量（QO 2）。我们被吸引去理解这种生理学， 早期糖尿病肾脏的生长、功能亢进和皮质PO 2降低可预测随后的损害， 下降在过去的15年里，我们已经确定了早期糖尿病患者肾小球和肾小管功能的特点， 特别强调肾小球滤过和近端重吸收如何相互影响。这 应用集中在饮食盐和已经在临床上的常见药物的肾脏效应上。 糖尿病护理设备。这些药物包括Na-葡萄糖协同转运蛋白SGLT 2的抑制剂， 胰高血糖素样肽1受体（GLP-1 R）激动剂。SGLT 2抑制剂和GLP-1 R激动剂正在 给数百万糖尿病患者服用，降低饮食盐将适用于数百万人，如果 公共卫生建议得到成功执行。每一个动作都有脱靶效果 对肾小球和肾小管功能的影响，我们打算研究其中的细微差别。目标是促进 通过提供生理学基础来发展有价值的假设， 为肾脏保护的临床试验提供科学解释， 已经在进行的审判。实验工作分为三个具体目标。每个目标都涉及 膳食盐、SGLT 2阻断和GLP-1 R激活对肾脏生理学特定方面的影响。 肾脏生理学的三个方面是1）近端小管生长和运输，2）肾脏血液动力学， （3）肾代谢。一个由运输、血流动力学和 代谢变量提供了对器官生理学的深入了解，而这些生理学是无法通过研究来确定的。 运输、血液动力学和新陈代谢。