PROJECT SUMMARY Chronic kidney disease (CKD) is the gradual decline in the kidneys capacity to filter excess fluid and waste from our blood. The main risk factors for CKD are high blood pressure (BP) and type 2 diabetes mellitus (T2D), which account for 73% of all CKD cases. Furthermore, 50-75% of all T2D patients will develop hypertension (HTN). The kidneys play a central role in blood pressure regulation through establishment of an individual’s BP set point. Pre-menopausal women have lower BP set points and lower incidence of cardiovascular disease (CVD) compared to age-matched males. This “female advantage” is also evident in milder phenotypes and slower disease progression observed in HTN, CVD and diabetic kidney disease (DKD) compared to males. Mechanisms accounting for this female advantage remain an important gap in our understanding of renal physiology. The overall goals of this proposal are to define sexual dimorphisms in key renal homeostatic mechanisms that impact BP, DKD and CVD using acute and chronic models of HTN in order to reduce incidence and improve therapeutics. AIM 1: Determine mechanisms and tubular locations responsible for the greater acute pressure natriuresis response in F vs M SD rats. I will utilize classic surgical procedures to increase blood pressure by vascular constriction to define sex-specific physiological responses and Na+ transporter regulation along the nephron. These experiments will provide insights into the mechanisms of the female advantage. AIM 2: Define the sexual dimorphisms in the renal tubular responses to HTN (lean M and F ZSF1) and T2D+HTN (obese M and F ZSF1 rats with early DKD). (2.1) A well-vetted and highly translational rat model of diabetic kidney disease will be used to investigate the sexual dimorphisms in progression of DKD including Na+ transporter regulation, fluid and electrolyte handling, renal injury markers, and metabolic biomarkers. Completion of aim will provide much-needed picture of the tubular responses to DKD progression in both sexes. The goal of the proposed research is to define key renal compensatory mechanisms in females to acute hypertension and the impact of diabetes with HTN in males and females. Overall, we aim to apply what we learn about the female advantage to males and post-menopausal females to inform treatments to reduce incidence and slow disease progression.