Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury

Abstract

Renal ischemia and reperfusion injury leads to acute renal failure when proinflammatory and apoptotic processes in the kidney are activated. The increase in hypoxia-inducible transcription factor-α (HIF-α), an important transcription factor for several genes, can attenuate ischemic renal injury. We recently identified a novel WD-repeat protein designated Morg1 (MAPK organizer 1) that interacts with prolyl hydroxylase 3 (PHD3), an important enzyme involved in the regulation of HIF-1α and HIF-2α expression. While homozygous Morg1 −/− mice are embryonic lethal, heterozygous Morg1 +/− mice have a normal phenotype. We show here that Morg1 +/− were partially protected from renal ischemia-reperfusion injury compared with wild-type Morg1 +/+ animals. Morg1 +/− mice compared with wild-type animals revealed a stronger increase in HIF-1α and HIF-2α expression in the ischemic-reperfused kidney associated with enhanced serum erythropoietin levels. However, no significant expression of HIF-1α and HIF-2α was found in nonischemic kidneys without any difference between Morg1 +/− and Morg1 +/+ mice. Ischemic kidneys of Morg1 +/− mice expressed more erythropoietin mRNA than ischemic kidneys from wild-type animals. Renal ischemia in Morg1 +/− mice resulted in a decrease in renal inflammation and reduction of proinflammatory cytokines (MCP-1, IP-10, MIP-2) compared with wild-type mice. Furthermore, there was significantly less apoptosis and tubular damage in Morg1 +/− kidneys after ischemia-reperfusion, and this was also reflected in significantly improved renal function compared with wild-type. Thus Morg1 may be a novel therapeutic target to limit renal injury after ischemia-reperfusion.