title: Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury.
abstract: Hypoxia-inducible transcription factors (HIF) protect cells against oxygen deprivation, and HIF stabilization before ischemia mitigates tissue injury. Because ischemic acute kidney injury (AKI) often involves the thick ascending limb (TAL), modulation of HIF in this segment may be protective. Here, we generated mice with targeted TAL deletion of the von Hippel-Lindau protein (Vhl), which mediates HIF degradation under normoxia, using Tamm-Horsfall protein (Thp)-driven Cre expression. These mice showed strong expression of HIF-1α in TALs but no changes in kidney morphology or function under control conditions. Deficiency of Vhl in the TAL markedly attenuated proximal tubular injury and preserved TAL function following ischemia-reperfusion, which may be partially a result of enhanced expression of glycolytic enzymes and lactate metabolism. These results highlight the importance of the thick ascending limb in the pathogenesis of AKI and suggest that pharmacologically targeting the HIF system may have potential to prevent and mitigate AKI.
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.forename: Frauke
authors.initials: F
authors.lastname: Forstreuter
authors.forename: Deepa
authors.initials: D
authors.lastname: Shukla
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
authors.forename: Seymour
authors.initials: S
authors.lastname: Rosen
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015308:Anaerobic Threshold / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000502:physiology; D006019:Glycolysis / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019426:Integrases / Q000235:genetics; D007668:Kidney / Q000502:physiology; D008138:Loop of Henle / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009393:Nephritis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D058949:Uromodulin / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C548613:Umod protein, mouse; D058949:Uromodulin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C045073:Cre recombinase; D019426:Integrases; C494469:VHL protein, mouse