Downregulation of Aquaporin-4 Protects Brain Against Hypoxia Ischemia via Anti-inflammatory Mechanism

Abstract

Aquaporin-4 (AQP4), a water-channel protein, controls water fluxes into and out of the brain parenchyma. The role of AQP4 in brain edema formation and resolution remains controversial. This study therefore determined the roles of AQP4 in brain edema and explored the underlying molecular mechanism. We established hypoxia-ischemia (HI) neonatal rat model in vivo and HI cell model in vitro, which were administrated with lentiviral or shRNA vector, respectively. We found that the neurologic deficit and motor dysfunction could be induced by HI with more serious brain damage after longer HI time, and swollen cells with enlarged surrounding space were observed after HI induction. The quantity of water in the brain tissues was significantly increased in the HI rats when compared with the control group. However, the downregulation AQP4 by lentiviral or shRNA vector reversed the brain edema and neurologic deficit induced by HI. The underlying mechanism of beneficial effects of AQP4 downregulation may be due to interactive regulation of AQP4 and inflammatory cytokines including IL-1β, IL-6, IL-10, and TNFα. Our data demonstrate that the silence of AQP4 results in a significant decrease in the expression of IL-1β, IL-10, and TNFα, but had no direct effect on IL-6 expression. AQP4 could indirectly regulate the expression of IL-6 via IL-1β, IL-10, and TNFα. In summary, these findings provide a novel mechanism to explain the role of AQP4 in HI pathogenesis and are instrumental for the development of treatment for HI-induced brain edema.