title: Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI.
abstract: Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxia-inducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI.
authors: Departments of Vegetative Physiology.
authors: Michael
authors: M
authors: Fähling
authors: Susanne
authors: S
authors: Mathia
authors: Alexander
authors: A
authors: Paliege
authors: Robert
authors: R
authors: Koesters
authors: Ralf
authors: R
authors: Mrowka
authors: Harm
authors: H
authors: Peters
authors: Pontus Börje
authors: PB
authors: Persson
authors: Hans-Hellmut
authors: HH
authors: Neumayer
authors: Sebastian
authors: S
authors: Bachmann
authors: Christian
authors: C
authors: Rosenberger
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis / Q000502:physiology; D053148:Caspase 3 / Q000032:analysis; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012206:Rhabdomyolysis / Q000150:complications*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse
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