title: Direct anti-inflammatory effects of angiotensin-(1-7) on microglia.
abstract: 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) (100-1000 nM, 3-12 h) 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)renin (PRO) (10-50 nM; 6 h) elicited significant increases in mRNAs for IL-1β, TNFα and CD11b. The effects of PRO (10 nM) 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. Renin-Angiotensin system mediated microglial activation and pro-inflammatory cytokine production within the hypothalamus are components of the chronic neuroinflammation associated with 'neurogenic' hypertension. We demonstrated that angiotension-(1-7) acting via its receptor Mas on hypothalamic microglia lessens baseline and (pro)renin-induced increases in pro-inflammatory cytokine production by these cells. This is the first evidence that angiotensin-(1-7) has direct anti-inflammatory effects via microglia.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: (pro)renin; hypothalamus; microglia; pro-inflammatory cytokine; renin-angiotensin system