Mechanism Of Sildenafil Regulating Renal Fibrosis In Mice Through Akt/gsk·3β Signaling Pathway

Objective:To investigate the regulation of sildenafil(Sil)on renal fibrosis in mice and provide experimental basis for the clinical application of Sil in UUO model renal fibrosis.Methods:90 Kunming mice were randomly divided into three groups,sham operation group(n=30).The mice only had ureteral separation,no ligation and cutting of the ureter,and lml/10g·d was given subcutaneous injection of 0.9%NaCl solution;UUO model group(n=30),UUO model group for mouse isolation and ligation of ureter;The UUO+Sil administration group(n=30),On the first day after the successful UUO model group,mice were injected Sil(12 mg/kg/d)at the same time every day for 14 days.On day 3,7 and 14 of the experiment,10 mice were randomly selected from each group.Eye blood was taken to determine serum SCr and BUN,After the execution,MDA and SOD were detected in kidney tissue,Pathological changes of renal tissue were observed by HE and Masson staining.Western blotting was used to determine Akt and GSK-3β proteins and their phosphoric acids in renal fibrosis expression level.Result:1.The contents of SCr and BUN in UUO model group were significantly higher than those in sham operation group(P<0.05).The contents of SCr and BUN in administration group were significantly lower than those in UUO model group(P<0.05).2.The MDA content UUO model group was higher than that in sham operation group(P<0.05),and the MDA content in administration group was lower than that in UUO model group(P<0.05).SOD activity in UUO model group was lower than that in sham operation group(P<0.05),and SOD activity in administration group was higher than that in UUO model group(P<0.05).3.UU03 days compared with sham operation group,partial renal tubular epithelial cell vacuolar degeneration was observed,with a small amount of renal tubular dilation accompanied by a small amount of inflammatory cell infiltration in UUO model group.At 7 days of UUO,renal tubular epithelial cells atrophy,tubular lumen dilation,interstitial widening and more inflammatory cell infiltration.The above changes were more obvious at UUO 14 days,renal interstitial fibroblast hyperplasia and interstitial fibrosis.The pathological changes in administration group were less severe than those in UUO model group.4.Compared with sham operation group,the collagen fibers in UUO model group increased gradually As time goes on.At UUO 3 days,You can see the tubular epithelial vacuolar degeneration.At UUO 7 days,pale blue collagen tissue was seen in partially widened stroma.At UUO 14 days,Parts of the widened stroma shows collagenous tissue.At UUO 14 days,the collagen fibers in the interstitium were significantly increased,the tubular epithelium was damaged,and the cells became pale with red staining.Administration group was less severe than UUO model group.5.Compared with sham operation group,the expression levels of p-Akt/Akt,p-GSK-3β/GSK-3β in UUO model group decreased gradually with the prolongation of obstruction time(P<0.05).Compared with administration group,the expression levels of p-Akt/Akt,p-GSK-3β/GSK-3β increased significantly(P<0.05).Conclusion:1.Sil can alleviate renal damage caused by renal fibrosis.2.Sil has an antioxidant effect on kidney tissue of UUO mice.3.Sil inhibits renal fibrosis in the UUO model,and its mechanism may be related to up-regulation of Akt/GSK3β pathway.