title: Hypoxia-inducible factor-1α dependent pathways mediate the renoprotective role of acetazolamide against renal ischemia-reperfusion injury.
abstract: OBJECTIVE
  Acute kidney injury (AKI) is a major complication of kidney transplantation, resulting in early graft dysfunction. Since diuretic acetazolamide (AZA) has been shown to improve contrast induced AKI, we hypothesized that AZA also protected against ischemia-reperfusion (I/R) caused AKI.
  
  
  METHODS
  An in vivo mouse renal I/R injury model and an in vitro H2O2 stimulated HK-2 cell injury model were utilized to examine the renoprotective effect of AZA. Renal injury and blood flow were measured. Nitric oxide synthase (eNOS)/Nitric oxide (NO), cell apoptosis and hypoxia-inducible factor-1α (HIF-1α) changes were analyzed.
  
  
  RESULTS
  AZA reduced kidney injury scores and improved renal function by decreasing serum creatinine and BUN levels after I/R. Impaired renal blood flow was restored by increasing eNOS activities and NO production, as indicated by Laser Doppler imaging. TUNEL staining presented that AZA reduced apoptotic cells due to attenuated caspase activation and increased Bcl-2/Bax ratio. Furthermore, HIF-1α induction by AZA was demonstrated. AZA also enhanced in vitro NO production, reduced cell apoptosis and increased HIF-1α expression. Knockdown of HIF-1α by RNAi confirmed that AZA exerted its protective role depending on HIF-1α. AZA's effects were significantly reduced by Akt inhibitor LY294002.
  
  
  CONCLUSIONS
  The present study demonstrated that AZA exerted a renoprotective role against I/R induced AKI through activating HIF-1α and downstream pathways.
authors: State Key Laboratory of Natural & Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors: Yu
authors: Y
authors: An
authors: Jian-zhao
authors: JZ
authors: Zhang
authors: Jing
authors: J
authors: Han
authors: Hao-peng
authors: HP
authors: Yang
authors: Lu
authors: L
authors: Tie
authors: Xiao-yuan
authors: XY
authors: Yang
authors: Yilixiati
authors: Y
authors: Xiaokaiti
authors: Yan
authors: Y
authors: Pan
authors: Xue-jun
authors: XJ
authors: Li
mesh_terms: D000086:Acetazolamide / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020011:Protective Agents; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D000086:Acetazolamide