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

Much evidence indicates that pro-inflammatory effects of the renin-angiotensin system 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 renin-angiotensin system, 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) (100-1000nM, 3-12h) elicited significant decreases in basal levels of mRNAs for the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor-necrosis factor (TNF) 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)renin (PRO) (10-50nM; 6h) elicited significant increases in mRNAs for IL-1, TNF and CD11b. The effects of PRO (10nM) on IL-1 and TNF mRNAs, and TNF protein, were significantly attenuated by co-treatment with Ang-(1-7) (100nM). Lastly, these actions of Ang-(1-7) were abolished by the Mas antagonist A-779, and were associated with reductions in NF-B subunit expression. Collectively, these data provide the first evidence that Ang-(1-7) can exert direct effects at microglia to lower baseline andcounteract PRO-induced increases in pro-inflammatory cytokines.