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Acetazolamide ameliorates renal ischemia-reperfusion injury via regulation of HIF-1α and aquaporin-1

【摘要】:正OBJECTIVE The study is to investigate whether acetazolamide(AZA) exerts a protective role against renal ischemia -reperfusion(IR) injury,as well as its possible protective mechanisms.METHODS In vivo study was conducted using C57BL/6 male mice to randomly divide animals into three groups:sham group,IR group and AZA treatment group.Mice in sham group were operated to only expose the kidneys to serve as a control.Mice in IR group underwent ischemia insult by occlusion of renal arteries and veins for 30min,then after 48 h of reperfusion mice were sacrificed for further examination.The operation of AZA treatment group was the same as IR group,however,mice were differently given AZA(60 mg·kg~(-1)·d~(-1),ig) and saline(ig) respectively.After sacrificing, mice kidneys were collected for histological analysis and western blot examination as well as other assays.In vitro study was examined by utilizing HK-2 cell line(human kidney epithelial cell line).To mimic ischemia-reperfusion injury,we treated HK-2 cells with H_2O_2 to induce oxidative stress injury.In this cell model,we observed the protective role of AZA via test of apoptosis pathway and NO concentration,more over,and the migration promoting effect of AZA by wound-healing assay and transwell assay.RESULTS Scr and BUN were increased in IR group,while in AZA treated group these indicators dropped.By examination of NO concentration both in vivo and in vitro,we demonstrated AZA promoted synthesis of NO and also increased the expression and activation of eNOS.HE staining showed AZA could prevent kidney from loss of integrity or dilation of tubules,and TUNEL staining showed apoptotic cells decreased dramatically.Caspase-3,cytoplasmic cytochrome c,Bax,and activity of casapse-8/9 was significantly increased in IR group, while AZA showed a reverse effect.By contrast,treatment of AZA significantly up-regulated anti-apoptotic molecule Bcl-2.Further to elucidate the eNOS and Bcl-2 modulating mechanism of AZA,We found AZA increased expression of their upstream transcription factor HIF-1α.In vitro study using HK-2 cells confirmed the change of these molecules.In addition,the underlying signaling mechanism analysis suggested PDK/Akt pathway play a crucial role in increase of HIF-1αafter AZA treatment.Using PI3K/Akt inhibitor LY294002 could mitigate the upregulation of HIF-1αand protective effect of AZA.Besides,we confirmed aquaporin-1(AQP1) in IR group decreased and returned after AZA treatment.At the same time,F-actin staining demonstrated AZA could promote survived epithelial cells migration by increasing protrusion-like structures.To test whether AZA influenced cells migration via regulating AQP1 in vitro,we showed AZA treatment had a role in promoting HK-2 cell migration by wound-healing assay and Transwell assay.However, AQP1 siRNA abolished promoting migration effect of AZA;AQP1 overexpression improved the migration of HK-2 cells after AZA treatment. CONCLUSION Our results firstly indicated AZA ameliorates renal IR injury via activating HIF-1αdependent eNOS and Bcl- 2 transcription and further promoting survival epithelial cells migration through regulating AQP1.The present study provides a new sight into treatment of renal IR injury and putative molecular targets for preventing kidneys from IR insults.

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