SIRT1-PGC-1? Pathway In The Pathogenesis Of Acute Kidney Injury In Cirrhosis

Background and Objective Acute kidney injury(AKI)is a common complication of patients with liver cirrhosis,with an incidence of up to 20%,high mortality and poor prognosis.The pathogenesis of AKI in cirrhosis is complex,and has not yet been fully clarified.SIRT1 is a nicotinamide adenine dinucleotide dependent deacetylase,which plays an important role in cell proliferation,differentiation,senescence,apoptosis and metabolism.PGC-1?is a direct downstream molecule of SIRT1.It has been found that the activation of SIRT1-PGC-1? can improve the function of mitochondria,which is closely related to the occurrence of AKI.Nevertheless,it is not clear about SIRT1-PGC-1? in the pathogenesis of AKI in cirrhosis.This study is aimed to explore the role of SIRT1-PGC-1? in the pathogenesis of AKI in cirrhosis animal,which may provide a new therapy target.Methods AKI of cirrhosis rats model was achieved by bile duct ligation(BDL)combined with intraperitoneal injection of lipopolysaccharide(LPS)(1mg/kg).Healthy,clean Sprague-Dawley rats were randomly divided into four groups: Sham(A group),Sham + LPS(B group),BDL(C group),and BDL + LPS(D group).Blood and tissue samples were measured after 3h of administration of LPS or saline,in the rats of either sham-operation or BDL 4 weeks ago.At last,thirty-two rats were left,A group(n=7),B group(n=7),C group(n=9),D group(n=9).Biochemical data of aspartate transaminas(AST),alanine aminotransferase(ALT),serum creatinine(Scr),and blood urea nitrogen(BUN)were measured.Tissue was used for pathologic examination and the expression of SIRT1 and PGC-1?were observed by Western blotting.Results(1)There was no statistical difference of AST,ALT,Scr,and BUN among four groups prior to sham-operation or BDL(P<0.05).ALT and AST increased sharply in group C and D(P<0.05),and have significant difference,compared with group A and B(P<0.05)after 4weeks.Scr was significantly higher after injection of LPS 3 hours later,which was statistically significant compared with group C(P<0.05).(2)Histopathological changes of liver tissue,including hepatocyte cords disorder,degeneration,lysis and necrosis,inflammatory cells infiltration,fibrosis and mild pseudolobuli were observed in groups C and D,but the tissue structure was normal in groups A and B.Renal tubular epithelial detachment and necrosis,along with inflammatory cells infiltration were observed in group D.In addition,the score of renal tissue injury in group D is significantly different from that in each other group(P<0.05).(3)Western-blot results showed that the protein level of SIRT1 and PGC-1? in renal tissue decreased significantly in group D compared with other groups(P < 0.05),and the correlation was statistically significant(r=0.893,P<0.01)Conclusions The expression level of SIRT1 and PGC-1? protein decreased in cirrhosis complicated by AKI,and their expression were correlated.Decreased SIRT1 level,therefore inhibiting PGC1-1? expression in kidney,may be one of the mechanisms that promote AKI in cirrhosis.It is suggested that activating SIRT1-PGC-1? signaling pathway can be an important potential target for the treatment of cirrhosis complicated by AKI.