Project Summary/Abstract It is well established that the incidence of hypertension increases with age. The prevalence of hypertension is higher in the aged (~62%) than in the young population (~11%). Salt sensitivity is more prevalent in the elderly population. The aging-related salt sensitivity is an important factor that contributes to the high prevalence of hypertension in the elderly population. Lysine (K)-specific demethylase 6a (KDM6A) is a recently-discovered powerful H3K27me3 demethylase. It is not known, however, if KDM6A is involved in the maintenance of blood pressure (BP). Whether KDM6A gene deficiency causes hypertension has never been determined. The objective of the proposed research is to determine whether KDM6A plays a role in the maintenance of BP and whether KDM6A gene deficiency is involved in the pathogenesis of hypertension. This objective will be achieved by pursuing two interrelated specific aims using a combination of several novel approaches including kidney- specific conditional gene knockout, epigenetic analysis, and in vivo kidney-specific gene delivery. The specific aims are: (1) Determine whether KDM6A plays a role in the regulation and maintenance of normal kidney function and blood pressure. (2) Determine whether in vivo expression of KDM6A attenuates aging-related impairment in renal Na excretion and hypertension. These studies will demonstrate, for the first time, an important role of KDM6A in the regulation of blood pressure and the pathogenesis of hypertension. The results will provide novel mechanism that KDM6A may protect the kidney. Completion of the project may reveal new insights into therapeutic strategies for hypertension and related cardiovascular disorder.