Angiotensin-(1-7) decreases LPS-induced inflammatory response in macrophages

J Cell Physiol. 2012 May;227(5):2117-22. doi: 10.1002/jcp.22940.

Abstract

It has been previously shown that besides its classical role in blood pressure control the renin-angiotensin system, mainly by action of angiotensin II on the AT(1) receptor, exerts pro-inflammatory effects such as by inducing the production of cytokines. More recently, alternative pathways to this system were described, such as binding of angiotensin-(1-7) to receptor Mas, which was shown to counteract some of the effects evoked by activation of the angiotensin II-AT(1) receptor axis. Here, by means of different molecular approaches we investigated the role of angiotensin-(1-7) in modulating inflammatory responses triggered in mouse peritoneal macrophages. Our results show that receptor Mas transcripts were up-regulated by eightfold in LPS-induced macrophages. Interestingly, macrophage stimulation with angiotensin-(1-7), following to LPS exposure, evoked an attenuation in expression of TNF-α and IL-6 pro-inflammatory cytokines; where this event was abolished when the receptor Mas selective antagonist A779 was also included. We then used heterologous expression of the receptor Mas in HEK293T cells to search for the molecular mechanisms underlying the angiotensin-(1-7)-mediated anti-inflammatory responses by a kinase array; what suggested the involvement of the Src kinase family. In LPS-induced macrophages, this finding was corroborated using the PP2 compound, a specific Src kinase inhibitor; and also by Western blotting when we observed that Ang-(1-7) attenuated the phosphorylation levels of Lyn, a member of the Src kinase family. Our findings bring evidence for an anti-inflammatory role for angiotensin-(1-7) at the cellular level, as well as show that its probable mechanism of action includes the modulation of Src kinases activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / immunology
  • Angiotensin I / pharmacology*
  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Cytokines
  • Lipopolysaccharides
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1
  • Angiotensin I
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • angiotensin I (1-7)