title: Morg1 heterozygous deficiency ameliorates hypoxia-induced acute renal injury.
abstract: Acute kidney injury is a common complication of critically ill patients and may occur as a result of various factors and coexisting previous illnesses. Some pathophysiological responses seen in critical illness can be similar to the human physiological response to extreme environmental challenges, such as hypoxia from reduced oxygen availability at high altitudes (systemic hypoxia). Due to oxygen deficiency, mammalian cells activate the transcriptional factor hypoxia-inducible factor (HIF); its degradation is regulated by prolyl hydroxylase 3 (PHD3) in interaction with the scaffold protein MAPK organizer 1 (Morg1). While homozygous Morg1(-/-) mice are embryonically lethal, the kidneys of heterozygous Morg1(+/-) mice reveal elevated HIF protein levels and increased serum erythropoietin compared with wild-type Morg1(+/+) mice. In this study, we exposed wild-type and Morg1(+/-) mice to 10% oxygen in a hypoxic chamber for 3 days. This reduced oxygen concentration leads to a deterioration of renal function, an increase in renal inflammation, and significantly more tubular damage and apoptosis in the kidneys of wild-type (Morg1(+/+)) mice. In sharp contrast, Morg1(+/-) kidneys were protected against systemic hypoxia. They show significantly less renal lesions, reduced or no inflammation, and less tubular damage and apoptosis. Thus short-term systemic and subsequently renal hypoxia which may occur in many patients in the intensive care unit induces in wild-type mice renal injury, which is ameliorated by Morg1 deficiency. Our findings suggest that therapeutical manipulation of Morg1 may be an interesting novel target to prevent hypoxia-associated renal damage.
authors.affiliation: Department of Internal Medicine III, University Hospital Jena, Jena, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Loeffler
authors.affiliation: Department of Internal Medicine III, University Hospital Jena, Jena, Germany Gunter.Wolf@med.uni-jena.de.
authors.forename: Gunter
authors.initials: G
authors.lastname: Wolf
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C487128:MORG1 protein, mouse
keywords: HIF-α; Morg1; acute renal injury; critical illness; systemic hypoxia