Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury.
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.
Hammerschmidt
Elke
E
Klinik für Innere Medizin III, Friedrich-Schiller-University, Jena, Germany.
Loeffler
Ivone
I
Wolf
Gunter
G
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004921:Erythropoietin / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D007668:Kidney / Q000196:embryology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology*; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C487128:MORG1 protein, mouse; D004921:Erythropoietin; D012313:RNA