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-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.

• Authors: Elke Hammerschmidt, Ivone Loeffler, Gunter Wolf
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 297 Issue 5 Pg. F1273-87 (Nov 2009) ISSN: 1522-1466 [Electronic] United States
• PMID: 19726548 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA, Complementary
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• MORG1 protein, mouse
• Erythropoietin
• RNA

Topics

• Acute Disease
• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Apoptosis (drug effects, physiology)
• Blotting, Western
• DNA, Complementary (biosynthesis, genetics)
• Electrophoretic Mobility Shift Assay
• Erythropoietin (biosynthesis, metabolism)
• Female
• Heterozygote
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Immunohistochemistry
• Kidney (embryology)
• Kidney Diseases (genetics, pathology)
• Kidney Function Tests
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pregnancy
• RNA (biosynthesis, genetics)
• Reperfusion Injury (genetics, pathology)
• Reverse Transcriptase Polymerase Chain Reaction