期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 32, 期 5, 页码 1151-1166出版社
KARGER
DOI: 10.1159/000354515
关键词
Acute Kidney injury; Kidney transplantation; Ischemia reperfusion; Acetazolamide; Hypoxia-inducible factor-1 alpha
资金
- National Natural Science Foundation of China [91129727, 81020108031, 30973558, 81270049, 81373405]
- Research Fund from Ministry of Education of China (111 Projects) [B07001]
Background/Aims: 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-1 alpha (HIF-1 alpha) 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-1 alpha induction by AZA was demonstrated. AZA also enhanced in vitro NO production, reduced cell apoptosis and increased HIF-1 alpha expression. Knockdown of HIF-1 alpha by RNAi confirmed that AZA exerted its protective role depending on HIF-1 alpha. 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-1 alpha and downstream pathways. Copyright (C) 2013 S. Karger AG, Basel
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