沉默交配型信息调节2同系物-1激活剂SRT1720对重度失血性休克/复苏大鼠急性肾损伤的治疗作用及机制

Protective effect and mechanism of SIRT1 activator SRT1720 on acute renal injury induced by severe hemorrhagic shock/resuscitation in rats

目的探讨沉默交配型信息调节2同系物-1(silent mating type information regulation2 homolog 1,SIRT1)激活剂SRT1720对重度失血性休克/复苏致大鼠急性肾损伤的治疗作用及机制。方法模型组、SIRT1激活剂SRT1720低、中、高剂量组(20、40、80mg/kg)建立重度失血性休克/复苏致大鼠急性肾损伤模型,建模成功后SIRT1激活剂SRT1720各剂量组给予相应药物,对照组、模型组给予等体积生理盐水;随后处死大鼠,测定肾/体比值、肌酐(SCr)、尿素氮(BUN)、肾脏SIRT1、信号转导转录激活剂-3(signal transducers and activators of transcription factor 3,STAT3)mRNA和蛋白水平、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平。结果与对照组比较,模型组肾/体比值、尿蛋白、SCr、BUN、IL-2、IL-6、TNF-α升高(t值分别为25.632、14.524、18.965、23.654、23.654、18.695、19.547,P均<0.001);与模型组比较,SRT1720各剂量组肾/体比值、尿蛋白、SCr、BUN、IL-2、IL-6、TNF-α降低(t=21.526、19.654、23.654、25.148,32.654、19.654、21.548、25.965、24.967、28.741、30.365、31.654、23.654、18.475、26.548、29.512,30.248、24.659、24.965、22.698、26.985,P均<0.001),且随着SRT1720给药剂量的增加,肾/体比值、尿蛋白、SCr、BUN、IL-2、IL-6、TNF-α逐渐降低,剂量-效应关系明显(t=38.632、19.625、25.847、27.489、26.954、29.547、32.685、34.489、32.362、24.548、29.654、28.415、35.957、32.548,P均<0.001)。与对照组比较,模型组肾SIRT1 mRNA和蛋白水平降低(t=38.635、32.145,P均<0.001),STAT3 m RNA水平升高(t=32.636、30.213,P均<0.001);与模型组比较,SRT1720各剂量组SIRT1 mRNA和蛋白水平升高(t=18.965、23.147、28.476、30.216、23.654、28.471,P均<0.001),STAT3 mRNA和蛋白水平降低(t=22.654、25.489、29.548、33.265、41.326、29.635,P均<0.001),且随着SRT1720给药剂量增加,SIRT1 m RNA和蛋白水平逐渐升高,STAT3 mRNA和蛋白水平逐渐降低,剂量-效应关系明显(t=27.485、28.459、30.215、29.584、29.654、31.145、32.159、30.269,P均<0.001)。结论SIRT1激活剂SRT1720能减轻重度失血性休克/复苏致大鼠急性肾损伤;其机制与SIRT1激活剂SRT1720通过激活大鼠肾脏中SIRT1表达,抑制STAT3表达进而抑制炎性介质表达有关。

Objective To explore the effect and mechanism of SRT1720,the activator of silent mating type information regulation 2 homolog-1(SIRT1),on severe hemorrhagic shock/resuscitation-induced acute kidney injury.Methods Rats were divided into control group,model group,SIRT1 activator SRT1720 low(20 mg·kg-1)group,medium(40 mg/kg)group,and high dose(80 mg/kg)group.Rats were then subjected to acute severe hemorrhagic shock/resuscitation to induced acute kidney injury.After establishment of the disease model,equal volume of normal saline was given to the rats in control and model group,and various doses of SRT1720 were given to the rats in SRT1720 low,medium and high groups.Rats were then sacrificed,and their kidney/body ratio,serum creatinine(SCr),urea nitrogen(BUN),SIRT1 in kidney,signal transducer and activator of transcription 3(STAT3)m RNA and protein,interleukin-2(IL-2),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)were measured.Results In model group,kidney/body ratio,urinary protein,SCr,BUN,IL-2,IL-6,and TNF-αincreased as compared with those in control group(t=25.632,14.524,18.965,23.654,23.654,18.695 and 19.547 respectively,P<0.001).In SRT1720 low,medium and high groups,kidney/body ratio,urinary protein,SCr,BUN,IL-2,IL-6,and TNF-αdecreased as compared with those in model group(t=21.526,19.654,23.654,25.148,32.654,19.654 and 21.548,respectively,in SRT1720 low group;25.965,24.967,28.741,30.365,31.654,23.654 and 18.475,respectively,in SRT1720 medium group;26.548,29.512,30.248,24.659,24.965,22.698 and 26.985,respectively,in SRT1720 high group;P<0.001);besides,SRT1720 dose and the lowering of the 7 biomarkers apparently have a dos Eresponse relationship(t=38.632,19.625,25.847,27.489,26.954,29.547 and 32.685,respectively,compared with those between SRT1720 low and medium groups;34.489,32.362,24.548,29.654,28.415,35.957 and 32.548,respectively,compared with those between SRT1720 medium and high groups;P<0.001).In model group,renal SIRT1 m RNA and protein decreased(t=38.635 and 32.145;P<0.001)and STAT3 m RNA and protein increased(t=32.636 and 30.213,P<0.001)as compared with those in control group.In SRT1720 low,medium and high groups,renal SIRT1 m RNA and protein increased(t=18.965 and 23.147 in SRT1720 low group;28.476 and 30.216 in SRT1720 medium group;23.654 and 28.471 in SRT1720 high group;P<0.001)and STAT3 m RNA and protein decreased(t=22.654 and 25.489 in SRT1720 low group;29.548 and 33.265 in SRT1720 medium group;41.326 and 29.635 in SRT1720 high group;P<0.001)as compared with those in model group;additionally,SRT1720 dose and the changes of the 4 biomarkers apparently have a dos Eresponse relationship(t=27.485,28.459,30.215 and 29.584,respectively,compared with those between SRT1720 low and medium groups;29.654,31.145,32.159 and 30.269,respectively,compared with those between SRT1720 medium and high groups,P<0.001).Conclusion The SIRT1 activator SRT1720 can alleviate acute renal injury induced by severe hemorrhagic shock/resuscitation in rats.The mechanisms may be that SRT1720 activates the expression of SIRT1 and inhibits the expression of STAT3 in kidney,through which the expressions of inflammatory mediators are inhibited.