Project Summary / Abstract Hypertension in patients with Metabolic Syndrome incurs a large financial, societal, and health cost in the United States. Despite several lines of evidence that hypertension in the Metabolic Syndrome has a distinct cause from idiopathic (essential) hypertension, this cause is not known and patients are treated empirically. Contributions from many labs over the last 30 years have supported the hypothesis that enhanced insulin signaling in the kidney plays a critical role in the pathogenesis of this disease. The Applicant's preliminary data confirms the hypothesis that insulin action in the kidney contributes to hypertension in a mouse model of Metabolic Syndrome and suggests that proximal tubular sodium transport may be increased, expanding blood volume, and increasing blood pressure. The Applicant has (1) characterized: a mouse model to study the intersection of the kidney, blood pressure, and Metabolic Syndrome and (2) generated a novel inducible tubule insulin receptor knockout mouse to study the contribution of insulin receptor signaling to sodium transport and blood pressure. In addition to the Applicant's contributions, the mentoring and scientific environment make him an ideal candidate to develop independence in renal physiology research addressing this important question. Here, the Applicant proposes three aims to study the contribution of insulin receptor signaling in the Metabolic Syndrome to acute pressure natriuresis (Aim 1), to regulators of proximal tubule sodium transporter activity in response to acute and chronic hypertension (Aim 2), and to patterns within the proximal tubule epithelial cell transcriptome generated by insulin receptor signaling, the Metabolic Syndrome, or both (Aim 3). Successful completion of these aims will begin to bridge the gap in knowledge between the role of insulin in whole animal physiology and transporter activity and regulation in individual cells. In addition, through this training mechanism the Applicant will learn the skills to successfully conduct independent research in basic science nephrology.