• Laura L Souza, Johan Duchene, Mihail Todiras, Luciano C P Azevedo, Claudio M Costa-Neto, Natalia Alenina, Robson A Santos, and Michael Bader.
• *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.
• Shock. 2014 Apr 1; 41 (4): 331-6.

AbstractThe 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.

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