[HTML][HTML] Hypoxia-inducible factor-1α dependent pathways mediate the renoprotective role of acetazolamide against renal ischemia-reperfusion injury

Y An, J Zhang, J Han, H Yang, L Tie, X Yang… - Cellular Physiology and …, 2013 - karger.com
Y An, J Zhang, J Han, H Yang, L Tie, X Yang, Y Xiaokaiti, Y Pan, X Li
Cellular Physiology and Biochemistry, 2013karger.com
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 H 2 O 2 stimulated HK-2 cell injury model were utilized to examine the
renoprotective effect of AZA. Renal injury and blood flow were measured. Nitric oxide …
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 H 2 O 2 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.
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