Direct anti-inflammatory effects of angiotensin-(1–7) on microglia

Abstract

Much evidence indicates that pro-inflammatory effects of the renin-angiotensin system (RAS) within the hypothalamus, including microglial activation and production of pro-inflammatory cytokines, play a role in chronic neurogenic hypertension. Our objective here was to examine whether angiotensin-(1–7) [Ang-(1–7)], a protective component of the RAS, exerts direct actions at microglia to counteract these pro-inflammatory effects. Mas, the Ang-(1–7) receptor, was shown to be present on cultured hypothalamic microglia. Treatment of these cells with Ang-(1–7) (100–1000 nM, 3–12h) elicited significant decreases in basal levels of mRNAs for the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor-necrosis factor α (TNFα) and of the microglia-macrophage marker CD11b, and increases in basal levels of the anti-inflammatory cytokine interleukin-10. Incubation of microglial cultures with PRO (10–50 nM; 6h) elicited significant increases in mRNAs for IL-1β, TNFα and CD11b. The effects of PRO (10nM) on IL-1β and TNFα mRNAs, and TNFα protein, were significantly attenuated by co-treatment with Ang-(1–7) (100 nM). Lastly, these actions of Ang-(1–7) were abolished by the Mas antagonist A-779, and were associated with reductions in NF-κB subunit expression. Collectively, these data provide the first evidence that Ang-(1–7) can exert direct effects at microglia to lower baseline and counteract PRO-induced increases in pro-inflammatory cytokines.