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.

Immune Mechanisms in Arterial Hypertension

“…Several groups have shown that adoptive transfer of Tregs lowers BP and ameliorates cardiac and renal injury in different models of hypertension. [65][66][67][68] Mice deficient in IL-10, an important product of Tregs, develop similar degrees of hypertension in response to angiotensin II, but have severe endothelial dysfunction and vessels from these mice show an increased superoxide production when incubated with angiotensin II. 69 These and other data suggest that Treg-derived IL-10 mediates the beneficial effects of Tregs in hypertension.…”

Hypertension as an autoimmune and inflammatory disease

“…16 Several experimental studies demonstrated the importance of regulatory T cells in the prevention of immune cell infiltration and the consequent development of hypertension. 44,45 Despite compelling evidence for T-cell involvement as part of the adaptive immune system in the generation and propagation of hypertension, it remains to be determined why T cells infiltrate the kidney, vascular wall and central nervous system. Is it simply a phenomenon secondary to chemokines produced from the reaction of the innate immune system, or is there a specific antigen, not yet identified, involved in the localized adaptive immune response?…”

Mechanism of Salt-Sensitive Hypertension

“…37 T-cell signaling is induced by chemokines and other stimulants and mediated by the activation of Rhoguanine triphosphate hydroxylases, such as Rac1. 38,39 Tregulatory lymphocytes prevent AII-and aldosterone-induced hypertension and vascular injury, 40 and crosstalk occurs between aldosterone and angiotensin signaling. 41 MR activation in macrophages contributes to BP elevation and vascular damages in AII/Nv-nitro-L-arginine methyl ester hypertension and deoxycorticosterone acetate (DOCA) salt hypertension.…”