Apoptosis contributes to the pro‐inflammatory T cell profile in blood of male and female spontaneously hypertensive rats, but not the control of blood pressure

Abstract

It is well established that cell death is a hallmark of hypertension. Apoptosis is a controlled physiologic form of cell death in which dying cells are cleared via phagocytosis limiting further tissue inflammation and damage. We have previously shown that spontaneously hypertensive rats (SHR) have greater apoptosis compared to age matched normotensive Wistar Kyoto rats. We also showed that there is a sex difference in renal cell death in SHR with females having greater renal apoptosis compared to age matched male SHR. The contribution of apoptosis to the control of blood pressure (BP) in established hypertension is unknown, however, 13 week old female SHR have a lower BP and a less pro‐inflammatory T cell profile compared to males. The goal of the current study was to test the hypothesis that greater apoptosis in female SHR contributes to the lower BP and anti‐inflammatory T cell profile vs. male SHR. Male (M) and female (F) SHR were randomized to receive vehicle (Veh) or ZVAD‐FMK, a cell permeable, non‐selective apoptosis inhibitor, from 13–15 weeks of age (1 mg/kg via IP injection 5 days/week; n=4–8) and BP was measured via telemetry. Following 2 weeks of treatment, kidney and blood were collected to measure apoptosis and the T cell profile by flow cytometry. Treatment with ZVAD for 2 weeks reduced renal apoptosis in both male and female SHR and abolished the sex difference in renal apoptosis (expressed as % total kidney cells‐ M Veh: 2.2±0.3 vs M ZVAD: 1.2±0.4; F Veh: 4.5±0.9 vs F ZVAD: 0.7±0.2; Effect of ZVAD: P<0.0001, Effect of sex: P=0.082, Interaction: P=0.0075). Inhibition of apoptosis did not alter BP in either male or female SHR (BP in mmHg in M ZVAD: 143±5; M Veh: 145±4 F ZVAD: 139±2; F Veh: 140±3 mmHg). However, inhibition of apoptosis decreased the numbers of circulating CD3+ T cells in both male (expressed as % total blood cells‐ M Veh: 12.2±1% vs M ZVAD: 10.3±1.1%) and female SHR (F Veh: 14.7±1.3% vs F ZVAD: 11.8±1.3%; Effect of ZVAD: P=0.07, Effect of sex: P=0.096, Interaction: P= 0.75). Inhibition of apoptosis also increased Tregs in female SHR (expressed as %CD3+CD4+FoxP3+ cells‐ F Veh: 6.3±0.3 vs F ZVAD: 8.1±0.1) with no effect in males (M Veh: 7.5±0.4% vs M ZVAD: 7.6±0.6%; Effect of ZVAD: P=0.025, Effect of sex: P=0.48, Interaction: P=0.041). The renal T cell profile was not altered by inhibition of apoptosis. Taken together, our data suggest that while apoptosis does not contribute to the control of BP in established hypertension in either male or female SHR, it does contribute to the pro‐inflammatory T cell profile in the blood of both sexes. Further studies will determine the contribution of apoptosis to the maturation induced increases in BP in SHR prior to the development of established hypertension.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.