Greater transforming growth factor-β in adult female SHR is dependent on blood pressure, but does not account for sex differences in renal T-regulatory cells.

Abstract

Female spontaneously hypertensive rats (SHR) have more renal regulatory T cells (Tregs) than males, and greater levels of Tregs in female SHR are dependent on blood pressure (BP). However, the molecular mechanism responsible for greater Tregs in female SHR is unknown. Transforming growth factor (TGF)-β is a pleiotropic cytokine critical in the differentiation of naïve T cells into Tregs, and female SHR have higher TGF-β excretion than male SHR. The goals of the current study were to test the hypotheses that 1) female SHR have greater renal TGF-β expression than male SHR, which is dependent on BP and 2) neutralizing TGF-β will decrease renal Tregs in female SHR. Renal cortices were isolated from 5- and 13-wk-old male and female SHR, and TGF-β levels were measured via Western blot and ELISA. Adult female SHR have more free, active TGF-β1 than 5-wk-old female SHR (46% more) or male SHR (44% more than 5-wk-old males and 56% more than 13-wk-old male SHR). We confirmed greater TGF-β1 in adult female SHR was due to increases in BP and not sexual maturation by measuring TGF-β1 levels following treatment with BP-lowering drugs or ovariectomy. Separate female SHR were treated with an antibody to TGF-β1,2,3; BP was measured, and T cells were assessed in whole blood and the kidney. Neutralizing TGF-β had no effect on BP, although circulating Tregs decreased by 32%, while Th17 cells increased by 64%. Renal Tregs were not altered by antibody treatment, although Th17 cells were decreased by 61%. In conclusion, although TGF-β promotes circulating Tregs in female SHR, it does not account for the sex difference in renal Tregs in SHR.