The Effect And Mechanism Of SRT1720 On Cisplatin-induced Kidney Injury

Objective: Cisplatin is a commonly used chemotherapy drug for the treatment of a variety of solid malignancies,including head and neck,breast,bladder,lung,ovarian,and testicular cancers.However,the clinical application of cisplatin is limited by its serious side effects,such as nephrotoxicity,myelosuppression,allergic reactions and peripheral neuropathy.Although the molecular basis of cisplatin-induced renal toxicity is not yet fully understood,previous studies have suggested that it is associated with the mechanisms of oxidative stress,inflammation,hypoxia,vascular injury and the activation of apoptotic pathways.SIRT1,a NAD+-dependent histone deacetylase,plays diverse roles in stress resistance,apoptosis,senescence and inflammation.In the present study,we investigate the role and mechanism of SRT1720 on cisplatin-induced kidney injury using mice model.Methods: Eight-week-old C57BL/6 male mice were randomly divided into three groups: control group(Control),cisplatin(Cis group)and cisplatin plus SRT1720 group(Cis+SRT).The dose of cisplatin induced acute kidney injury in mice was 20 mg/kg(dissolved in normal saline),and administered by intraperitoneal injection.Mice in the Cis+SRT group were treated with 50 mg/kg SRT1720 daily by gavage from three days before cisplatin administration continues to be killed.Blood urea nitrogen and creatinine levels were measured in blood.HE was used to detect renal tissue morphology changes.TUNEL staining was used to detect apoptosis.Immunohistochemistry was used to detect the expression of SIRT1,Bax,Bcl-2,F4/80 and MCP-1.Western blot was used to detect the expression of SIRT1,Bax,Bcl-2,NOX4,SOD,GPX,NF-?B p65,p-p38 MAPK and p38 MAPK in kidneys.Results:1.Compared with normal control group,the expression of SIRT1 in the kidney of mice treated with cisplatin for 3 days was significantly reduced.The cisplatin-induced SIRT1 expression was enhanced by SRT1720 in kidney of mice.2.Compared with the control group,the levels of serum creatinine and urea nitrogen in the cisplatin group were increased.SRT1720 significantly reduced serum creatinine and urea nitrogen levels in mice induced by cisplatin.3.A few apoptotic cells were observed in the kidney of normal control mice.After 3 days of cisplatin intervention,kidney cell apoptosis and Bax/Bcl-2 ratio were significantly increased.SRT1720 inhibited cisplatin-induced apoptosis and Bax/Bcl-2 ratio in kidneys.4.F4/80 positive cells were rare in the normal control group,and the number of F4/80 positive cells increased after cisplatin intervention for 3 days.SRT1720 reduced cisplatin-induced F4/80 expression in kidney.5.Compared with the normal control group,the expressions of MCP-1 protein,and MCP-1,TNF-?,IL-6 and IL-1? m RNA were significantly increased in kidney after treatment with cisplatin for 3 days.SRT1720 inhibited the expression of MCP-1 protein,and MCP-1,TNF-?,IL-6 and IL-1? m RNA expression kidney induced bycisplatin.6.Compared with the normal control group,the expression of NF-?B p65 in the nucleus of kidney was significantly increased in the cisplatin group.SRT1720 significantly inhibited the nuclear expression of NF-?B p65 induced by cisplatin.7.Compared with the normal control group,the expression of NOX4 was significantly increased,and the expression of SOD and GPX was significantly decreased in the kidney in cisplatin group.Compared with the cisplatin group,the expression of NOX4 was significantly reduced,while the expression of SOD and GPX were increased in kidney in SRT1720 treatment group.8.Compared with the normal control group,the expression of p-p38 MAPK in the kidney was significantly increased in cisplatin group.SRT1720 inhibited the expression of p-p38 MAPK induced by cisplatin.Conclusions: SRT1720 protects against cisplatin-induced kidney damage may be by regulating oxidative stress,apoptosis,inflammatory response and activation of the p38 MAPK signaling pathway.