The Temporal Effects of DOCA‐Salt on the Renal T Cell Profile is Sex‐Specific

Abstract

There is growing evidence for a role for T cells in the pathogenesis of hypertension. Previous studies by our laboratory show that hypertensive males have more pro‐inflammatory Th17 cells while females have more anti‐inflammatory T regulatory cells (Tregs); we propose that greater Tregs in females contribute to their lower blood pressure (BP) compared to males. The goal of the current study was to test the hypothesis that Tregs preferentially increase over time in female rats with increases in BP, while Th17 cells will increase to a greater extent in males. Male (M) and female (F) uni‐nephrectomized Sprague Dawley rats (10 weeks of age) were subcutaneously implanted with a deoxycorticosterone acetate (DOCA) pellet (200 mg/rat, 60‐day time release) and given 0.9% NaCl to drink. Subsets of rats were killed following 1, 2, and 3 weeks (wks) of DOCA treatment and kidneys were processed for flow cytometric analysis of T cells; n=6/group per time point. BP was measured in separate DOCA rats via telemetry (n=5–6). DOCA increased BP in both M (basal: 115±4, wk1: 146±3, wk2: 187±2, wk3: 190±2 mmHg; p<0.01) and F rats (basal: 105±3, wk1: 134±5, wk2: 165±8, wk3: 175±8 mmHg; p<0.01). BP was comparable between the sexes at baseline (p=0.2), wk 1 (p=0.07) and wk 3 (p=0.1); M had a higher BP than F at wk 2 (p=0.03). At all time points, females had more Tregs than males, and males had more Th17 cells (effect of sex: p<0.05 for all comparisons). Neither Tregs nor Th17 cells were altered vs. control following 1 wk of DOCA treatment (effect of treatment: p=0.9 for both). After 2 wks of DOCA treatment, Tregs decreased in treated males vs. control but were maintained in females (interaction: p=0.06) and Th17 cells increased in both sexes, although the increase was greater in males (effect of DOCA: p<0.001; interaction: p=0.02). Finally, at wk 3 of treatment, DOCA increased Tregs (effect of DOCA: p<0.01) and Th17 cells (effect of DOCA: p=0.03) in both sexes. We propose that the sex‐specific effects of DOCA on T cells at wk 2 contribute to sex differences in BP. The ability of females to maintain Tregs and thereby limit increases in effector Th17 cells at this time point may be a critical pathway by which they are able to maintain a lower BP relative to males.Support or Funding InformationR01HL127091‐02 Male Control Male DOCA Female Control Female DOCA Tregs: Wk 1 4±0.5 4±0.6 5±0.6 5±0.5 Tregs: Wk 2 5±0.8 3±0.5* 6±0.9 7±0.7 Tregs: Wk 3 2±0.3 4±0.3* 4±0.5 7±0.6* Th17 cells: Wk 1 16±2 17±1 11±1 11±1 Th17 cells: Wk 2 6±0.6 27±3* 4±0.5 17±1* Th17 cells: Wk 3 17±1 21±3* 11±2 17±3* All data are expressed as percent of CD3+CD4+ cells; indicates p<0.05 vs. same sex control.