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Blood pressure impacts the renal T cell profile of male and female spontaneously hypertensive ratsOf the 68 million Americans with hypertension, fewer than 46% have their blood pressure (BP) adequately controlled and women are more likely than men to have uncontrolled hypertension. This underscores the critical need for new treatment options; however, this is a challenge due to our lack of knowledge regarding the mechanism(s) driving essential hypertension. T cells have been implicated in hypertension in males. Prior to our work, the role of T cells in hypertensive females had been unexplored. We demonstrate that female spontaneously hypertensive rats (SHR) have a decrease in BP in response to an immunosuppressant, supporting an immune component to their hypertension. We further defined a sex difference in the renal T cell and cytokine profile in SHR. Female SHR have a more anti-inflammatory immune profile in their kidneys than males. To gain insight into the mechanisms mediating sex differences in the immune profile, male and female SHR were gonadectomized. Gonadectomy increased pro-inflammatory markers in both sexes and attenuated anti-inflammatory markers particularly in females. Therefore, while both male and female sex hormones promote an anti-inflammatory immune profile, female ii sex hormones contribute greater to their more anti-inflammatory profile, but do not explain the sex difference. To determine the impact of hypertension on the renal immune profile, experiments measured renal T cells and cytokines in hypertensive male and female SHR, normotensive Wistar Kyoto rats (WKY), and SHR treated with antihypertensive therapy. All T cells and cytokines measured were higher in SHR compared to the same sex WKY. Moreover, antihypertensive therapy decreased renal Tregs only in female SHR. These data suggest that increased BP in both sexes is associated with an increase in renal inflammation; however female SHR have a compensatory increase in renal Tregs in response to increases in BP. TGF-β is a key cytokine regulating Treg and Th17 differentiation and we found that female SHR express more TGF-β than males. Experiments assessed if female SHR possessed a sex hormone or BP-mediated increase in renal TGF- β corresponding with increases in Tregs. We determined that loss of female sex hormones and increased BP in female SHR increase renal TGF-β expression. We conclude that BP status drive sex differences in the renal T cell and cytokine profile of SHR.
Sex Differences in Renal Inner Medullary Nitric Oxide Synthase Regulation and Nitric Oxide Synthase Contribution to Blood Pressure Control in HypertensionThere are sex differences in the development of hypertension with young males developing a more severe pathology faster than age-matched females; however, with advancing age this “protection” in females is lost. The mechanisms responsible for the sex difference in hypertension are unclear but the vasodilator nitric oxide (NO)/NO synthase (NOS) pathway which is important in blood pressure (BP) regulation has been implicated. Systemic inhibition of NOS using L-NAME (2, 5, and 7 mg/kg/day at 4 days per dose in drinking water) in male and female spontaneously hypertensive rats (SHR) resulted in dose-dependent increases in BP measured via telemetry; however, females exhibited greater increases in BP than males. Treatment of male and female SHR chronically with L-NAME at a dose of 7 mg/kg/day for 2 weeks significantly increased BP in both sexes, however, a previous exposure to L-NAME increased BP sensitivity to chronic NOS inhibition in females exclusively; this confirmed our hypothesis that female SHR are more dependent on NOS for BP control compared to male. Important for BP control, the renal inner medulla (IM) is the only region of the kidney to exhibit sex differences in NOS enzymatic activity. Female SHR have greater total NOS activity than males and we observed that it is not due to differences in phosphorylation or protein expression. Therefore, we examined potential molecular mechanisms to explain the sexual dimorphism in renal IM NOS activity. The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) has been indicated in hypertension. However, HPLC analysis of ADMA and the essential NOS substrate L-arginine were equal between the sexes in plasma and renal IM of SHR and thus do not contribute to the sex differences in renal IM NOS activity. Tetrahydrobiopterin (BH4) is an essential NOS cofactor and decreased BH4 availability has been indicated to be elevated in patients and animal models with essential hypertension. BH4 levels can be decreased via oxidation and male SHR have higher levels of oxidative stress compared to females. HPLC analysis of biopterin levels in control and tempol (antioxidant) treated SHR showed that female SHR have greater total biopterin, BH4 and BH2 levels than males in the renal IM and that these sex differences were dependent on the presence of oxidative stress. Studies next examined if greater biopterin levels in females translated into greater NOS activity in females. In vitro analysis of NOS enzymatic activity confirmed that greater oxidative stress and deficiency of BH4 of male SHR in the renal IM resulted in lower levels of NOS activity relative to female SHR. In addition, in vitro analysis of renal IM NOS activity revealed that 1) female SHR exhibit a sex hormone-dependent increase in renal IM NOS activity from sexually immature, pre-hypertensive age to sexually mature, hypertensive age that is not evident in male SHR and 2) that the ability of female sex hormones to stimulate NOS activity is time-dependent. In conclusion, the combination of BH4 deficiency in males caused by elevated oxidative stress and the ability of female sex hormones to stimulate NOS activity in female SHR and not ADMA or L-arginine, contribute to the sexual dimorphism in renal IM NOS activity. In addition, differences in sensitivity to NOS levels in SHR aid in creating sex differences in BP control.