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: 9384689
• 负责人: SCOTT Culver THOMSON
• 金额: $ 43.85万
• 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/9384689
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Agonist; Antidiabetic Drugs; Blood Glucose; Blood Pressure; Caring; Clinical; Clinical Trials; Coupling; Diabetes Mellitus; Diet; Electron Transport; Elements; Equilibrium; Fibrosis; 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 salt; exenatide; experimental study; glomerular filtration; hemodynamics; in vivo; inhibitor/antagonist; insight; 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.

项目摘要摘要 肾脏在身体器官中是独一无二的，因为它可以通过大大而大的糖尿病反应 增加其功能和氧气消耗（QO2）。我们被吸引理解这种生理学，因为 早期糖尿病性肾脏中的生长，过度功能和低皮质PO2预测随后的损害和 衰退。在过去的15年中，我们表征了早期糖尿病的肾小球和管状功能 肾脏特别强调肾小球过滤和近端重吸收如何相互影响。这 应用的重点是饮食中盐的肾脏作用和已经存在的常见药物 糖尿病护理的武术。这些药物包括Na-葡萄糖共转运蛋白sglt2和 胰高血糖素样肽1受体（GLP-1R）的激动剂。 SGLT2抑制剂和GLP-1R激动剂正在 给予数百万糖尿病患者的管理，饮食中盐的降低将适用于数百万，如果 公共卫生建议成功实施。这些操纵中的每一个都有脱靶效果 在肾小球和管状功能上，我们打算研究的细微差别。目标是促进 通过为发展值得的假设提供生理学的基础来获取医学知识 进行临床试验以进行肾脏保护，并提供有关此类结果的科学解释 已经进行的试验。实验工作分为3个特定目标。每个目标都解决 饮食盐，SGLT2阻滞和GLP-1R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）近端管状生长和运输，2）肾脏血流动力学， 3）肾脏代谢。从运输，血液动力学和 代谢变量为无法通过研究确定的有机生理学提供了见识 孤立的运输，血液动力学和代谢。