According to updated hypertension guidelines, ~46% of all American adults have hypertension, a primary risk factor for heart disease which is the leading cause of death. The mechanisms causing hypertension remain unknown and less than 50% of patients taking blood pressure (BP)-lowering medications have their BP controlled. There are also well-established sex differences in hypertension, where young males have greater increases in BP vs. age-matched females; however the mechanisms underlying sex differences in BP are still being investigated. Our goal is to address critical gaps concerning the mechanisms that drive the development of hypertension in both sexes by advancing our understanding of the role of cell death in hypertension. Our central hypothesis is that male sex hormones preferentially promote renal tubular necrosis in hypertensive males vs. females. Our hypothesis is supported by strong preliminary data showing 1) comparable renal necrosis in sexually immature 6 wk old male and female spontaneously hypertensive rats (SHR), 2) greater renal necrosis in 13 wk old sexually mature male vs. female SHR, and 3) greater renal tubular cell death in 13 wk old male SHR vs. females. Our central hypothesis will be tested by two specific aims. Aim 1 will test the hypothesis that male sex hormones drive greater renal necrosis and the expression of necrotic cell death machinery in male SHR. Experiments will measure renal necrosis and cell death machinery in gonad-intact and gonadectomized (GDX) male and female SHR. Experiments will also determine the contribution of testosterone to renal necrosis in both sexes and the contribution of testosterone vs. BP to renal necrosis. Studies in aim 2 will test the hypothesis that renal tubular cells in males are more susceptible to necrotic cell death vs. cells from females. Experiments will confirm renal tubular necrosis and assess the relative susceptibility of freshly isolated tubular cells from male and female SHR to hydrogen peroxide-induced necrosis. Understanding why males have more necrosis than females and which cells are most susceptible to hypertension-induced necrosis will provide novel insight into the mechanisms causing hypertension. Moreover, our proposed studies have the potential to explain fundamental differences in BP control between the sexes since sex differences in cell death may represent a unifying mechanism underlying sex difference in many hypertensive stimuli.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|