T Regulatory Lymphocytes Prevent Aldosterone-Induced Vascular Injury

Abstract

Aldosterone mediates actions of the renin-angiotensin-aldosterone system inducing hypertension, oxidative stress, and vascular inflammation. Recently, we showed that angiotensin II–induced hypertension and vascular damage are mediated at least in part by macrophages and T-helper effector lymphocytes. Adoptive transfer of suppressor T-regulatory lymphocytes (Tregs) prevented angiotensin II action. We hypothesized that Treg adoptive transfer would blunt aldosterone-induced hypertension and vascular damage. Thirteen to 15-week–old male C57BL/6 mice were injected intravenously at 1-week intervals with 3×10 5 CD4 + CD25 + cells (representing Treg) or control CD4 + CD25 − cells and then infused or not for 14 days with aldosterone (600 μg/kg per day, SC) while receiving 1% saline to drink. Aldosterone induced a small but sustained increase in blood pressure ( P <0.001), decreased vasodilatory responses to acetylcholine by 66% ( P <0.001), increased both media:lumen ratio ( P <0.001) and media cross-sectional area of resistance arteries by 60% ( P <0.05), and increased NADPH oxidase activity 2-fold in aorta ( P <0.001), kidney and heart ( P <0.05), and aortic superoxide production. As well, aldosterone enhanced aortic and renal cortex macrophage infiltration and aortic T-cell infiltration (all P <0.05), and tended to decrease Treg in the renal cortex. Treg adoptive transfer prevented all of the vascular and renal effects induced by aldosterone. Adoptive transfer of CD4 + CD25 − cells exacerbated aldosterone effects except endothelial dysfunction and increases in media:lumen ratio of resistance arteries. Thus, Tregs suppress aldosterone-mediated vascular injury, in part through effects on innate and adaptive immunity, suggesting that aldosterone-induced vascular damage could be prevented by an immunomodulatory approach.