Glomerular and Tubular Function in the Diabetic Kidney

项目总结摘要 肾脏在人体器官中是独一无二的，因为它对早期糖尿病的反应是通过增大和 增加其功能和氧耗(QO2)。我们被吸引去理解这种生理学是因为 早期糖尿病肾脏的生长、功能亢进和低皮质氧分压可预测随后的损害和 拒绝。在过去的15年中，我们研究了早期糖尿病患者的肾小球和肾小管功能。 特别强调肾小球滤过和近端重吸收如何相互影响。这 应用的重点是饮食盐和常见药物的肾脏影响，这些药物已经在 糖尿病护理的大本营。这些药物包括钠葡萄糖共转运体SGLT2的抑制剂和 胰升糖素样肽1受体激动剂(GLP-1R)。SGLT2抑制剂和GLP-1R激动剂正在 给数百万糖尿病患者服用，而降低食盐将适用于另外数百万人，如果 公共卫生建议得到成功落实。每一种动作都有偏离目标的效果 对肾小球和肾小管功能的影响，我们打算研究它们的细微差别。其目标是促进 通过为开发有价值的假说提供生理学基础来获得医学知识 为肾脏保护提供临床试验，并对这种试验的结果提供科学解释 已经在进行中的试验。实验工作分为三个具体目标。每个目标都针对 饮食盐、SGLT2阻断和GLP-1R激活对肾脏生理的一个特定方面的影响。 肾脏生理学的三个方面是：1)近端肾小管的生长和运输，2)肾血流动力学， (3)肾脏代谢。由交通、血液动力学和交通之间的因果关系组成的网络 代谢变量为研究无法确定的有机生理学提供了洞察力 运输、血流动力学和新陈代谢的隔离。

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.