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.