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: Gunnar Schley, Bernd Klanke, Johannes Schödel, Frauke Forstreuter, Deepa Shukla, Armin Kurtz, Kerstin Amann, Michael S Wiesener, Seymour Rosen, Kai-Uwe Eckardt, Patrick H Maxwell, Carsten Willam
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 22 Issue 11 Pg. 2004-15 (Nov 2011) ISSN: 1533-3450 [Electronic] United States
• PMID: 21921145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Umod protein, mouse
• Uromodulin
• Von Hippel-Lindau Tumor Suppressor Protein
• Cre recombinase
• Integrases
• VHL protein, mouse

Topics

• Acute Kidney Injury (genetics, metabolism, physiopathology)
• Anaerobic Threshold (physiology)
• Animals
• Disease Models, Animal
• Erythropoiesis (physiology)
• Glycolysis (physiology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Integrases (genetics)
• Kidney (physiology)
• Loop of Henle (physiology)
• Mice
• Mice, Mutant Strains
• Nephritis (genetics, metabolism, physiopathology)
• Reperfusion Injury (genetics, metabolism, physiopathology)
• Uromodulin (genetics, metabolism)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)