Glomerular and Tubular Function in the Diabetic Kidney

项目摘要 主要肾脏葡萄糖转运蛋白SGLT 2的抑制剂已被证明可以减缓糖尿病的进展。 慢性肾脏疾病（CKD）伴或不伴糖尿病。然而，主要的知识差距 仍然取决于这些药物如何作用于肾脏。知识缺口包括SGLT 2抑制剂如何改变肾脏 微血管功能、肾小管系统和肾脏代谢。观察到的特征 全肾水平的治疗是从微观水平的事件中产生的，治疗在微观水平上有直接的效果。 微观水平。然而，微观行为不能从全肾行为推断出来，必须 直接观察。这不能在人类中完成，但可以在人类肾脏的大鼠和小鼠模型中完成 使用调查人员擅长的专门技术造成的伤害。通过这些研究方法， 确定SGLT 2抑制剂对肾脏内部工作的影响。其中包括一个拟议的 传出小动脉舒张，可能对GFR没有任何影响，但总是减少滤过 分数和增加O2输送到肾脏。研究将确定SGLT 1作为靶向药物的潜力， 保护肾脏的新治疗策略。我们将确定SGLT 2抑制剂是否具有脱靶效应， 对肾脏的影响，这已经被提议用于心脏。我们将比较 这些药物在实验和临床样品中。我们的目标是描绘代谢组学， 这些药物在它们靶向的非常管状的细胞中的蛋白质组特征，即，早期近端小管， 将这些效应与暴露于更多葡萄糖的下游肾小管细胞中的反应进行比较， 药物作用。我们的目标是全面了解这些药物如何影响健康和 以更好地了解它们的治疗益处。

PROJECT SUMMARY ABSTRACT Inhibitors of the principle kidney glucose transporter, SGLT2, have been shown to slow the progression of chronic kidney disease (CKD) in the presence or absence of diabetes mellitus. However, major knowledge gaps remain in how these drugs act on the kidney. Knowledge gaps include how SGLT2 inhibitors alter kidney microvasculature functions, the tubular system, and kidney metabolism. Features that are observed at the whole-kidney level emerge from events at the microscopic level and treatments have their direct effect at the microscopic level. Microscopic behavior, however, cannot be deduced from whole-kidney behavior and must be observed directly. This cannot be done in humans but can be done in rat and mouse models of human kidney injury using specialized techniques at which the investigators are expert. By these methods this research will determine the effects of SGLT2 inhibitors on the inner workings of the kidney. This includes a proposed relaxation of the efferent arteriole, which may not have any effect on GFR but it always reduces filtration fraction and increases O2 delivery to the kidney. Studies will determine potential for targeting of SGLT1 as a new therapeutic strategy to protect the kidney. We will determine whether SGLT2 inhibitors have off-target effects in the kidney, which have been proposed for the heart. We will compare the metabolomics signature of these drugs in both experimental and clinical samples. And we aim to delineate the metabolomic and proteomic signature of these drugs in the very tubular cells they target, i.e., the early proximal tubule, but also compare these effects with responses in downstream tubular cells exposed to more glucose as a consequence of drug action. Our goal is an integrated understanding how these drugs impinge on the kidney in the healthy and diseased kidney to better understand their therapeutic benefits.