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Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury.
J Am Soc Nephrol
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.
|Title:||Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury.|
|Keywords:||Acute Kidney Injury, Anaerobic Threshold, Animals, Disease Models, Animal, Erythropoiesis, Glycolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Integrases, Kidney, Loop of Henle, Mice, Mice, Mutant Strains, Nephritis, Reperfusion Injury, Uromodulin, Von Hippel-Lindau Tumor Suppressor Protein|
|UCL classification:||UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)
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