title: Receptor MAS protects mice against hypothermia and mortality induced by endotoxemia.
abstract: The renin-angiotensin (Ang) system is involved in maintaining cardiovascular function by regulating blood pressure and electrolyte homeostasis. More recently, alternative pathways within the renin-angiotensin system have been described, such as the ACE-2/Ang-(1-7)/Mas axis, with opposite effects to the ones of the ACE/Ang-II/AT1 axis. Correspondingly, our previous work reported that Ang-(1-7) via its receptor Mas inhibits the mRNA expression of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α increased by lipopolysaccharide (LPS) in mouse peritoneal macrophages. These data led us to investigate the functional role of the Ang-(1-7)/Mas axis in an in vivo LPS model. In this work, we present evidence that Ang-(1-7) via Mas significantly reduced the LPS-increased production of circulating cytokines, such as IL-6, IL-12, and CXCL-1. This inhibitory effect was mediated by Mas because it was not detectable in Mas-deficient (Mas) mice. Accordingly, IL-6, CXCL-1, and CXCL-2 levels were higher after LPS treatment in the absence of Mas. Mas mice were less resistant to LPS-induced endotoxemia, their survival rate being 50% compared with 95% in wild-type mice. Telemetric analyses showed that Mas mice presented more pronounced LPS-induced hypothermia with a 3°C lower body temperature compared with wild-type mice. Altogether, our findings suggest that Ang-(1-7) and Mas inhibit LPS-induced cytokine production and hypothermia and thereby protect mice from the fatal consequences of endotoxemia.
authors.affiliation: *Max-Delbrück Center for Molecular Medicine; and †Charité-University Medicine, Berlin, Germany; and ‡Department of Biochemistry and Immunology, Faculty of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto; §Teaching and Research Institute, Sirio-Libanes Hospital, São Paulo; and ∥Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Souza
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.forename: Mihail
authors.initials: M
authors.lastname: Todiras
authors.forename: Luciano C P
authors.initials: LC
authors.lastname: Azevedo
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Costa-Neto
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Robson A
authors.initials: RA
authors.lastname: Santos
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
mesh_terms: D000803:Angiotensin I / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism; D007035:Hypothermia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; C118790:angiotensin I (1-7)