Renin liberated from MCP‐1/CCL2‐activated mast cells initiates the systemic inflammation of alveolar hypoxia

Abstract

Alveolar hypoxia (AH) produces widespread systemic inflammation in rats. This inflammation is not initiated by low systemic tissue PO2, but by the alveolar macrophage (AMØ)-borne-MCP-1/CCL2, which, in turn, stimulates tissue mast cells (MC) and the local renin-angiotensin-system (RAS). The activation of RAS occurs downstream of MC degranulation. Since renin is the enzyme that catalyzes the first and rate-limiting step of RAS, we hypothesized that renin released from MC initiates the activation of RAS. The expression of renin in peritoneal MC (PMC) was demonstrated by immunocytochemistry. PMC renin is active since the renin blocker-WFML (3 μM) significantly decreased the formation of Ang II induced by 30ng/ml MCP-1 from 725 ± 60 pg/ml to 153 ± 14 pg/ml in MC cultured in normal plasma. Moreover, MCP-1-induced generation of Ang II was abolished by pretreatment of ACE inhibitor-captopril (1mM). These results indicate that the formation of Ang II in MC is mainly via the ACE, rather than the MC chymase pathway. Further studies carried out in MC cultured in DMEM in the presence of Ang I showed that captopril also abolished Ang II formation induced by the MC secretagogue-compound 48/80. Since ACE is not contained in DMEM, it follows it must be contained in MC. Conclusions Hypoxia stimulates AMØ to release MCP-1, which activates MC. Activated MC liberate renin and ACE to generate Ang II. Supported by HL39443