| Objective:To investigate the effect of liraglutide on renal injury and the renal expression of FoxO1 in type 2 diabetic rats.Methods:Male Sprague Dawley(SD)rats were randomly divided into normal diets group(NC group,n=8)and high sucrose-fat diets group(n=27).The NC group rats were fed with normal diets until the end of the experiment,while high sucrose-fat diets group rats were fed with high sucrose-fat diets throughout the study.8 weeks later,the rats in high sucrose-fat diets group were intraperitoneally injected with 30 mg/kg of Streptozotocin(STZ)after fasting 12 hours,while rats in NC group were intraperitoneally injected with equal citrate buffer.After 72 hours,rats with the fasting blood glucose concentrations ?11.1mmol/L for three continuous days were considered as diabetic.Five weeks after the injection of STZ,diabetic rats were randomly divided into diabetic nephropathy control group(DN group,n=8)and liraglutide treatment group(DN +LIRA group,n=8).There were 8 rats in the NC group.Rats in DN + LIRA group received liraglutide subcutaneously(200?g/kg,twice a day),while rats in NC group and DN group were given subcutaneously with a equal dose of normal saline.Tail-vein fasting blood glucose(FBG)levels were measured weekly.After 8 weeks,24 h urine samples were collected using individual metabolic cages for measuring urinary albumin and creatinine;glycosylated hemoglobin(HbA1c),serum creatinine(Scr),blood urea nitrogen(BUN)were measured;pathomorphology changes of glomeruli were observed by the light and electron microscope;the expression of transforming growth factor-beta 1(TGF-?1),fibronectin(FN),type ? collagen(Col ?),forkhead transcription factor O1(FoxO1),manganese superoxide dismutase(MnSOD)mRNA were detected using real time PCR;the expression of p-FoxO1 and TGF-?1 protein in glomeruli were detected by immunohistochemical staining.Results:1.After 8 weeks treatment,compared with NC group,the FBG,HbA1 c,kidney index(KI)were significantly elevated(all P<0.05),and body weight was significantly decreased in DN group(P<0.05).The FBG,HbA1 c,KI in DN+LIRA group were lower than those in DN group(all P<0.05),but there was no significant differences in the body weight between DN group and DN+ LIRA group(P>0.05).2.5 weeks after the injection of STZ,the urinary albumin/creatinine ratio(ACR)was significantly increased in the DN group and DN+ LIRA group compared with the NC group(all P<0.05),and there was no significant differences between DN group and DN+ LIRA group(P>0.05).At the end of the study,compared with NC group,the ACR,Scr and BUN were significantly elevated in the DN group(all P<0.05);but the ACR,Scr and BUN in DN+LIRA group were lower than those in DN group(all P<0.05).There was no significant differences in the BUN between NC group and DN+ LIRA group(P>0.05).3.PASM staining showed glomerular hypertrophy,mesangial cell proliferation,mesangial expansion in the DN group compared with the NC group.In contrast,compared with the DN group,the pathological changes were remarkably improved in the DN+ LIRA group.Electron microscopy revealed the ultrastructural abnormalities including glomerular basement membrane(GBM)thickening,podocyte foot process fusion in the DN group,however,these abnormalities were improved in the DN+ LIRA group compared with the DN group.4.Compared with the NC group,the expressions of TGF-?1,FN and Co ? mRNA in renal tissues were significantly increased in the DN group(all P<0.05).While the three fibrosis indicators were significantly lower in the DN+ LIRA group than those in the DN group(all P<0.05).Compared with the NC group,the expressions of FoxO1 and MnSOD mRNA in renal tissues were significantly decreased in the DN group(all P<0.05),but the two indicators were significantly higher in the DN+ LIRA group than those in the DN group(all P<0.05).5.Compared with the NC group,the expressions of TGF-?1 and p-FoxO1 protein in glomeruli were significantly elevated in the DN group(all P<0.05).While the expressions of TGF-?1 and p-FoxO1 protein in glomeruli were significantly lower in the DN+ LIRA group than those in the DN group(all P<0.05).6.Correlation analysis: ACR was positively correlated with the percentage of positive staining area of TGF-?1(r=0.880,P<0.05)and p-FoxO1(r=0.841,P<0.05).The ratio of the mesangial matrix area/glomerular tuft area was positively correlated with the percentage of positive staining area of TGF-?1(r=0.823,P<0.05)and p-FoxO1(r=0.815,P<0.05).Conclusions:Liraglutide may exert a renoprotective effect on diabetic nephropathy by a FoxO1-mediated upregulation of renal MnSOD expression in type 2 diabetic rats. |
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