CELL DEATH CONTRIBUTES TO SEX DIFFERENCES IN THE CONTROL OF BLOOD PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS (SHR).

Abstract

Cell death is a hallmark of hypertension; however, little is known regarding sex differences in cell death in hypertension. The goal of Aim 1 was to determine if there are sex differences in cell death in young adult spontaneously hypertensive rats (SHR). Cell death was measured by flow cytometric analysis in the kidney, spleen and thoracic aorta. We found greater renal necrosis in male SHR compared to females. Whereas female SHR had greater renal and aortic apoptosis compared to males. Necrosis is a pathologic form of cell death, whereas apoptosis is a physiologic form of cell death. The contribution of cell death to the reported sex differences in renal T cell profile or the control of blood pressure (BP) in either sex is unknown. Therefore, studies in Aims 2 and 3 were designed to determine the contributions of necrosis (Aim 2) and apoptosis (Aim 3) to the development of hypertension, control of BP in established hypertension, and the renal T cell profile in both male and female SHR. We found that necrosis, but not apoptosis contributes to the control of BP and the development of hypertension in male, but not female SHR. In addition, necrosis, but not apoptosis contributed to the pro-inflammatory renal T cell profile in SHR, although to a comparable degree in both sexes. The goal of Aim 4 was to gain additional mechanistic insight into why males had greater necrosis vs. females. It is well-established that the male sex hormone testosterone contributes to the sex differences in BP in SHR. Therefore, Aim 4 was designed to determine the relative contributions of testosterone vs. high BP on renal necrosis in male SHR. To achieve this, male SHR were subjected to surgical castration prior to sexual maturation or treated with BP-lowering drugs prior to the development of hypertension. We found that testosterone, but not high BP contributes to renal necrosis when compared to sham male SHR. The massive workload imposed on renal tubular epithelial cells (TECs) requires them to consume high amounts of energy and studies showed that TECs from male SHR are more prone to stress-induced cell death compared to TECs from male Wistar Kyoto rats (WKY). Additional studies in Aim 4 were further designed to determine if TECs isolated from male SHR are more prone to oxidative stress-induced necrotic cell death when compared to cells from females. TECs from males showed greater necrotic cell death compared to cells from age-matched female SHR. From these studies, we conclude that male SHR exhibit a testosterone-mediated increase in renal necrotic cell death which contributes to the sex differences in BP in SHR by exacerbating increases in BP in male, but not female SHR. Targeting necrotic cell death in males could allow for better control of BP to reduce overall cardiovascular morbidity and mortality.