Quantcast

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

Research paper by Elke E Hammerschmidt, Ivone I Loeffler, Gunter G Wolf

Indexed on: 04 Sep '09Published on: 04 Sep '09Published in: American journal of physiology. Renal physiology



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-alpha (HIF-alpha), 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-1alpha and HIF-2alpha 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-1alpha and HIF-2alpha expression in the ischemic-reperfused kidney associated with enhanced serum erythropoietin levels. However, no significant expression of HIF-1alpha and HIF-2alpha 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.