靶向线粒体肽对碘造影剂致高胆固醇血症大鼠急性肾损伤的保护作用
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摘要
背景：造影剂急性肾损伤(Contrast media-induced acute kidney injury,CIAKI)已成为当前院内发生急性肾损伤(Acute kidney injury,AKI)的第三位常见原因,研究表明氧化应激在CIAKI中起重要作用,NADPH氧化酶是产生活性氧的主要来源；靶向线粒体肽能清除细胞内活性氧,减少细胞线粒体ROS产生,抑制脂质过氧化；然而NADPH氧化酶及靶向线粒体肽在CIAKI中的作用未见文献报道。
目的：研究氧化应激、NADPH氧化酶和线粒体能量代谢在高胆固醇血症大鼠CIAKI中的作用；探讨靶向线粒体肽(MTP131,SPI20)对高胆固醇血症大鼠CIAKI的保护作用及机制。
方法：40只雄性SD大鼠随机分为先将大鼠随机分为两组：正常饮食组8只(NN组),高胆固醇饮食组32只(H组,4%胆固醇和1%胆酸钠)。正常组大鼠因低体重死亡一只,高胆固醇饮食组死亡四只,继续高胆固醇饮食的大鼠随机分为4组,每组7只,分别为高胆固醇饮食组(HN组)、高胆固醇饮食+造影剂组(HH组)、高胆固醇饮食+造影剂+MTP131(HM组)、高胆固醇饮食+造影剂+SPI20(HS组)。NN组和HN组大鼠分别从尾静脉注射等量生理盐水10ml/kg,HH组、HM组和HS组大鼠从尾静脉注射(76%泛影葡胺)造影剂,注射剂量均为10ml/kg,建立高胆固醇血症大鼠造影剂急性肾损伤模型。HM组和HS组大鼠在注射造影剂前24 h和30min及注射造影剂后24h分别经腹腔注射MTP131和SPI20(每次3 mg/kg)。注射造影剂前和后48 h收集尿标本,经眼球取血,检测尿肌酐、尿钾、尿钠和血清肌酐、血钾、血钠、血胆固醇、血甘油三酯。注射造影剂后48 h,采用10%水合氯醛(3mL/kg)腹腔注射麻醉后处死大鼠,取左肾制备肾组织匀浆,分别用于测脂质过氧化产物丙二醛(MDA)、超氧化物歧化酶(SOD)和ATP酶活性；取右肾下极组织采用10%福尔马林固定,石蜡包埋、切片,HE染色,观察肾脏的病理改变；其余部分装入冻存管中,保存于液氮中用于提取组织蛋白检测肾组织NADPH氧化酶活性及Western blot检测肾组织NOX4表达。
结果：注射造影剂前,与NN组比较各组大鼠血胆固醇水平显著增高(P<0.01),各组大鼠体重、血清肌酐、血甘油三酯、内生肌酐清除率、钾钠排泄分数差异均无统计学意义。注射造影剂后48h,与NN组比较,HN组大鼠血清肌酐、肾小管损伤分数和肾组织NADPH氧化酶活性增高(P值分别P<0.05,P<0.001,P<0.001)；HH组大鼠血清肌酐、钾钠排泄分数、肾组织匀浆MDA含量明显升高(P<0.01),肾小管损伤分数和肾组织NADPH氧化酶活性显著增高(P<0.001),内生肌酐清除率、肾组织匀浆SOD和ATP酶活性显著下降(P<0.01),肾组织NOX4蛋白表达明显上调(P<0.05)。与HN组比较,HH组大鼠血清肌酐、钾钠排泄分数、肾组织匀浆MDA含量、肾小管损伤分数、肾组织NADPH氧化酶活性明显升高(P<0.01),内生肌酐清除率、肾组织匀浆SOD和ATP酶活性下降(P<0.05),肾组织NOX4蛋白表达上调(P<0.05)。与模型组比较,MTP131和SPI20干预组大鼠血清肌酐、钾钠排泄分数、肾脏组织匀浆MDA含量显著降低(P<0.05),肾组织匀浆SOD和ATP酶活性显著升高(P<0.05),肾小管损伤分数明显减少(P<0.001),肾组织NADPH氧化酶活性及NOX4蛋白表达下调(P值分别P<0.001,P<0.05)。
结论：氧化应激、NADPH氧化酶和线粒体能量代谢在高胆固醇血症大鼠CIAKI中起重要作用；靶向线粒体肽MTP131和SPI20对高胆固醇血症大鼠CIAKI有保护作用,其机理可能与抗氧化、清除脂质过氧化物,降低肾组织NADPH氧化酶活性,下调肾组织NOX4表达及保护线粒体ATP酶有关。
Background:contrast media-induced acute kidney injury(CIAKI) has become the third common cause of hospital-acquired acute kidney injury.There is growing evidence suggests that reactive oxygen species (ROS) play an important role in CIAKI and NADPH-oxidase is a major source of ROS production.Mitochondria-targeted peptides can scavenge ROS,reduce mitochondrial ROS production and inhibite lipid peroxidation. However, It is not clear whether mitochondria-targeted peptides protect CIAKI.
Objective:To explore the role of oxidative stress,NADPH-oxidase and mitochondrial energy metabolism in CIAKI rats with environment of hypercholesterolemia and to investigate the protective effect of mitochondria-targeted peptides (MTP131,SPI20).
Methods:Forty healthy SD male rats were randomly divided into normal dietary group (group NN, n= 8) and high cholesterol supplemented dietary group (group H,4% cholesterol and 1% cholic acid,n=32).At the end of 8 weeks,one of normal group was too weak to survive,four rats with high cholestoral diet lost weight and finally died, the remains with high cholesterol diet were randomly divided into four subgroups (7/group),namely high cholesterol diet group(group HN),high cholesterol plus contrast media diatrizoate group (group HH),high cholesterol plus diatrizoate plus MTP131 group(MTP protective group, group HM),high cholesterol plus diatrizoate plus SPI20 group (SPI20 protective group,group HS).Seven rats from each diet feeding were given a tail vein injection of either diatrizoate with 10ml/kg or equal volume of normal saline,the rats of MTP131 or (SPI 20) protective group were given with MTP131 or SPI 20 (3mg/kg) by peritoneal cavity injection 3 times (24 h before and after contrast media injection and half hour just before contrast media administration).Forty-eight hours before and after contrast media injection,blood and urine samples were prepared to determine total cholesterol,triglyceride,serum, creatinine, creatinine,clearance(Ccr), fractional excretion of sodium and potassium levels.Forty-eight hours after contrast media injection, the rats were executed. The malonadehyde (MDA),superoxide dismutase(SOD), activity of ATPase and NADPH oxidase of kidney tissue were measured. The expression of NOX4 was assessed by Western blot. The renal injury was assessed by HE staining.
Results:Before injection of contrast medium, An increase of cholesterol was observed in all rats with high cholesterol diet group. Compare to the group NN, the Scr, renal tubular injury scores and NADPH oxidase activity of kidney tissue increased in the rats of group HN (P<0.05,P<0.001,P<0.001,respectively).In group HH, the Scr, FeNa%,FeK%,MDA level of kidney homogenate were higher and the CCr,renal SOD level, ATPase activity were lower than those of group NN (P<0.01);the renal tubular injury scores, NADPH oxidase activity and expression of NOX4 in kidney tissue were significantly greater than those of group NN (P<0.001,P<0.05,respectively).Compare with the group HN, the Scr, FeNa%, FeK%, MDA level of kidney homogenate,renal tubular injury scores and renal NADPH oxidase activity of group HH also increased (P<0.01),the CCr, renal SOD and ATPase activity decreased and the expression of NOX4 in kidney tissue upregulated (P<0.05).Mitochondria-targeted peptides MTP131 and SPI20 could downregulate level of Scr, FeNa%, FeK% and MDA content in kidney homogenate (P<0.05),upregulate the renal SOD and ATPase activity (P<0.05);The renal tubular injury scores, NADPH oxidase activity and expression of NOX4 were decreased (P<0.001，P<0.05,respectively).
Conclusion:Oxidative stress, NADPH oxidase and mitochondrial energy metabolism play an important role in CIAKI rats with environment of hypercholesterolemia. MTP131 and SPI20 might play a protective role in CIAKI rats with environment of hypercholesterolemia, the mechanisms may be related to anti-oxidant, scavenge lipid peroxides, reduce NADPH oxidase activity, suppress the expression of NOX4 protein in kidney and protect mitochondrial ATPase.
目的：研究氧化应激、NADPH氧化酶和线粒体能量代谢在高胆固醇血症大鼠CIAKI中的作用；探讨靶向线粒体肽(MTP131,SPI20)对高胆固醇血症大鼠CIAKI的保护作用及机制。
方法：40只雄性SD大鼠随机分为先将大鼠随机分为两组：正常饮食组8只(NN组),高胆固醇饮食组32只(H组,4%胆固醇和1%胆酸钠)。正常组大鼠因低体重死亡一只,高胆固醇饮食组死亡四只,继续高胆固醇饮食的大鼠随机分为4组,每组7只,分别为高胆固醇饮食组(HN组)、高胆固醇饮食+造影剂组(HH组)、高胆固醇饮食+造影剂+MTP131(HM组)、高胆固醇饮食+造影剂+SPI20(HS组)。NN组和HN组大鼠分别从尾静脉注射等量生理盐水10ml/kg,HH组、HM组和HS组大鼠从尾静脉注射(76%泛影葡胺)造影剂,注射剂量均为10ml/kg,建立高胆固醇血症大鼠造影剂急性肾损伤模型。HM组和HS组大鼠在注射造影剂前24 h和30min及注射造影剂后24h分别经腹腔注射MTP131和SPI20(每次3 mg/kg)。注射造影剂前和后48 h收集尿标本,经眼球取血,检测尿肌酐、尿钾、尿钠和血清肌酐、血钾、血钠、血胆固醇、血甘油三酯。注射造影剂后48 h,采用10%水合氯醛(3mL/kg)腹腔注射麻醉后处死大鼠,取左肾制备肾组织匀浆,分别用于测脂质过氧化产物丙二醛(MDA)、超氧化物歧化酶(SOD)和ATP酶活性；取右肾下极组织采用10%福尔马林固定,石蜡包埋、切片,HE染色,观察肾脏的病理改变；其余部分装入冻存管中,保存于液氮中用于提取组织蛋白检测肾组织NADPH氧化酶活性及Western blot检测肾组织NOX4表达。
结果：注射造影剂前,与NN组比较各组大鼠血胆固醇水平显著增高(P<0.01),各组大鼠体重、血清肌酐、血甘油三酯、内生肌酐清除率、钾钠排泄分数差异均无统计学意义。注射造影剂后48h,与NN组比较,HN组大鼠血清肌酐、肾小管损伤分数和肾组织NADPH氧化酶活性增高(P值分别P<0.05,P<0.001,P<0.001)；HH组大鼠血清肌酐、钾钠排泄分数、肾组织匀浆MDA含量明显升高(P<0.01),肾小管损伤分数和肾组织NADPH氧化酶活性显著增高(P<0.001),内生肌酐清除率、肾组织匀浆SOD和ATP酶活性显著下降(P<0.01),肾组织NOX4蛋白表达明显上调(P<0.05)。与HN组比较,HH组大鼠血清肌酐、钾钠排泄分数、肾组织匀浆MDA含量、肾小管损伤分数、肾组织NADPH氧化酶活性明显升高(P<0.01),内生肌酐清除率、肾组织匀浆SOD和ATP酶活性下降(P<0.05),肾组织NOX4蛋白表达上调(P<0.05)。与模型组比较,MTP131和SPI20干预组大鼠血清肌酐、钾钠排泄分数、肾脏组织匀浆MDA含量显著降低(P<0.05),肾组织匀浆SOD和ATP酶活性显著升高(P<0.05),肾小管损伤分数明显减少(P<0.001),肾组织NADPH氧化酶活性及NOX4蛋白表达下调(P值分别P<0.001,P<0.05)。
结论：氧化应激、NADPH氧化酶和线粒体能量代谢在高胆固醇血症大鼠CIAKI中起重要作用；靶向线粒体肽MTP131和SPI20对高胆固醇血症大鼠CIAKI有保护作用,其机理可能与抗氧化、清除脂质过氧化物,降低肾组织NADPH氧化酶活性,下调肾组织NOX4表达及保护线粒体ATP酶有关。
Background:contrast media-induced acute kidney injury(CIAKI) has become the third common cause of hospital-acquired acute kidney injury.There is growing evidence suggests that reactive oxygen species (ROS) play an important role in CIAKI and NADPH-oxidase is a major source of ROS production.Mitochondria-targeted peptides can scavenge ROS,reduce mitochondrial ROS production and inhibite lipid peroxidation. However, It is not clear whether mitochondria-targeted peptides protect CIAKI.
Objective:To explore the role of oxidative stress,NADPH-oxidase and mitochondrial energy metabolism in CIAKI rats with environment of hypercholesterolemia and to investigate the protective effect of mitochondria-targeted peptides (MTP131,SPI20).
Methods:Forty healthy SD male rats were randomly divided into normal dietary group (group NN, n= 8) and high cholesterol supplemented dietary group (group H,4% cholesterol and 1% cholic acid,n=32).At the end of 8 weeks,one of normal group was too weak to survive,four rats with high cholestoral diet lost weight and finally died, the remains with high cholesterol diet were randomly divided into four subgroups (7/group),namely high cholesterol diet group(group HN),high cholesterol plus contrast media diatrizoate group (group HH),high cholesterol plus diatrizoate plus MTP131 group(MTP protective group, group HM),high cholesterol plus diatrizoate plus SPI20 group (SPI20 protective group,group HS).Seven rats from each diet feeding were given a tail vein injection of either diatrizoate with 10ml/kg or equal volume of normal saline,the rats of MTP131 or (SPI 20) protective group were given with MTP131 or SPI 20 (3mg/kg) by peritoneal cavity injection 3 times (24 h before and after contrast media injection and half hour just before contrast media administration).Forty-eight hours before and after contrast media injection,blood and urine samples were prepared to determine total cholesterol,triglyceride,serum, creatinine, creatinine,clearance(Ccr), fractional excretion of sodium and potassium levels.Forty-eight hours after contrast media injection, the rats were executed. The malonadehyde (MDA),superoxide dismutase(SOD), activity of ATPase and NADPH oxidase of kidney tissue were measured. The expression of NOX4 was assessed by Western blot. The renal injury was assessed by HE staining.
Results:Before injection of contrast medium, An increase of cholesterol was observed in all rats with high cholesterol diet group. Compare to the group NN, the Scr, renal tubular injury scores and NADPH oxidase activity of kidney tissue increased in the rats of group HN (P<0.05,P<0.001,P<0.001,respectively).In group HH, the Scr, FeNa%,FeK%,MDA level of kidney homogenate were higher and the CCr,renal SOD level, ATPase activity were lower than those of group NN (P<0.01);the renal tubular injury scores, NADPH oxidase activity and expression of NOX4 in kidney tissue were significantly greater than those of group NN (P<0.001,P<0.05,respectively).Compare with the group HN, the Scr, FeNa%, FeK%, MDA level of kidney homogenate,renal tubular injury scores and renal NADPH oxidase activity of group HH also increased (P<0.01),the CCr, renal SOD and ATPase activity decreased and the expression of NOX4 in kidney tissue upregulated (P<0.05).Mitochondria-targeted peptides MTP131 and SPI20 could downregulate level of Scr, FeNa%, FeK% and MDA content in kidney homogenate (P<0.05),upregulate the renal SOD and ATPase activity (P<0.05);The renal tubular injury scores, NADPH oxidase activity and expression of NOX4 were decreased (P<0.001，P<0.05,respectively).
Conclusion:Oxidative stress, NADPH oxidase and mitochondrial energy metabolism play an important role in CIAKI rats with environment of hypercholesterolemia. MTP131 and SPI20 might play a protective role in CIAKI rats with environment of hypercholesterolemia, the mechanisms may be related to anti-oxidant, scavenge lipid peroxides, reduce NADPH oxidase activity, suppress the expression of NOX4 protein in kidney and protect mitochondrial ATPase.
引文
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[37].Lee HB,Yu MR,Yang Y,et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol.2003,14:241-245
[38].Francesco P.Pathogenetic mechanisms of diabetic nephropathy.J Am Soc Nephrol,2005,16:30～33
[39].Whaley-Connell A,Habibi J,Nistala R.Attenuation of NADPH oxi dase activation and glomerular filtration barrier remodeling with statin treatment. Hypertension.2008,51(2):474～480.
[40].马骏,姜文霞,王慧芳等.缺血和血管活性物质对肾脏Na+,K+-ATP酶活性的影响.第二军医大学学报.2004,25(2)：182-184
[41].Brooks C, Wei Q, Cho SG,et al.Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.J Clin Invest. 2009;119(5):1275～1285.
[42].Chiu PY, Leung HY, Ko KM.Schisandrin B Enhances Renal Mitochondrial Antioxidant Status, Functional and Structural Integrity, and Protects against Gentamicin-Induced Nephrotoxicity in Rats.Biol Pharm Bull.2008, 31(4):602～605.
[43].Xu F, Papanayotou I, Putt DA,et al.Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-L-cysteine in primary cultures of human proximal tubular cells.Biochem Pharmacol.2008,76(4):552～567.
[44].Feldkamp T, Kribben A, Weinberg JM.F1FO-ATPase activity and ATP dependence of mitochondrial energization in proximal tubules after hyp oxia/reoxygenation.J Am Soc Nephrol.2005,16(6):1742～1751.
[45].Szeto HH.Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury.Antioxid Redox Signal.2008,10(3):601～619.
[46].Duong MH,MacKenzie TA,Malenka DJ.N-acetylcysteine prophylaxis significantly reduces the risk of radiocontrast-induced nephropathy: comprehensive meta-analysis.Catheter Cardiovasc Interv.2005,64(4):471～479.
[47].Drager LF,Andrade L,Barros de Toledo JF,et al.Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy:decrease in oxidant stress-mediated renal tubular injury.Nephrol Dial Transplant.2004,19(7):1803～1807.
[48].Heinrich MC, Haberle L, Muller V,Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media:meta-ana lysis of randomized controlled trials.Radiology.2009;250(1):68-86.
[49].Solomon R.Preventing contrast-induced nephropathy:problems, challenges and future directions.BMC Med.2009,13(7):24-26
[50].Zhao K,Luo G,Giannelli S,et al.Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines.Biochem Pharmacol.2005,70:1796～1806.
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[40].马骏,姜文霞,王慧芳等.缺血和血管活性物质对肾脏Na+,K+-ATP酶活性的影响.第二军医大学学报.2004,25(2)：182-184
[41].Brooks C, Wei Q, Cho SG,et al.Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.J Clin Invest. 2009;119(5):1275～1285.
[42].Chiu PY, Leung HY, Ko KM.Schisandrin B Enhances Renal Mitochondrial Antioxidant Status, Functional and Structural Integrity, and Protects against Gentamicin-Induced Nephrotoxicity in Rats.Biol Pharm Bull.2008, 31(4):602～605.
[43].Xu F, Papanayotou I, Putt DA,et al.Role of mitochondrial dysfunction in cellular responses to S-(1,2-dichlorovinyl)-L-cysteine in primary cultures of human proximal tubular cells.Biochem Pharmacol.2008,76(4):552～567.
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[45].Szeto HH.Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury.Antioxid Redox Signal.2008,10(3):601～619.
[46].Duong MH,MacKenzie TA,Malenka DJ.N-acetylcysteine prophylaxis significantly reduces the risk of radiocontrast-induced nephropathy: comprehensive meta-analysis.Catheter Cardiovasc Interv.2005,64(4):471～479.
[47].Drager LF,Andrade L,Barros de Toledo JF,et al.Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy:decrease in oxidant stress-mediated renal tubular injury.Nephrol Dial Transplant.2004,19(7):1803～1807.
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[1].Andrikos E,Tseke P,Balafa O,et al.Epidemiology of acute renal failure in ICUs:a multi-center prospective study.Blood Purif,2009,28(3):239～244.
[2].Garcia-Tsao QParikh CR,Viola A.Acute kidney injury in cirrhos is.Hepatology,2008,48:2064～2077.
[3].Khalil P,Murty P,Paul M,et al.The Patient with Acute Kidney Injury.Prim Care Clin Office Pract.2008,35:239～264.
[4].Chawla LS,Abell L,Mazhari R,et al.Identifying critically ill patients at high risk for developing acute renal failure:a pilot study.Kidney Int.2005,68:2274-2280.
[5].Macedo E,Castro I,Yu L,et al.Impact of mild acute kidney injury (AKI) on outcome after open repair of aortic aneurysms.Ren Fail,2008,30:287-296.
[6].Rosner MH,Okusa MD.Acute kidney injury associated with cardiac surgery.Clin J Am Soc Nephrol,2006,1:19～32.
[7].Byers J,Sladen RN.Renal function and dysfunction.Curr Opin Anaes thesiol.2001,14:699～706.
[8].Schrier RW,Wang W.Acute renal failure and sepsis.N Engl J Med. 2004,351:159～169.
[9].段绍斌,刘伏友,彭佑铭,等.造影剂对慢性肾功能不全患者肾毒性.肾脏病与透析肾移植杂志,2001,10(2)：130～132.
[10].Scolari F,Tardanico R,Zani R,et al.Cholesterol crystal embolism:a recognizable cause of renal disease.Am J Kidney Dis,2000,36:1089～1109.
[11].Davidson MB,Thakkar S,Hix JK,et al.Pathophysiology,clinical consequences,and treatment of tumor lysis syndrome.Am J Med.2004,116:546～554.
[12].Modi KS,Rao VK.Atheroembolic renal disease.J Am Soc Nephrol. 2001,12:1781～1787.
[13].Seabra VF,Balk EM,Liangos O,et al.Timing of renal replacement therapy initiation in acute renal failure:A Meta-analysis[J].Am J Kidney Dis,2008,52: 272～284
[14].Bouman CS,Oudemans-Van Straaten HM,Tijssen JG et al.Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure:A prospective,randomized trial.Crit Care Med,2002,30:2205-2211.
[15].Cho KC,Himmelfarb J, Paganini E,et al.Survival by dialysis modality in critically ill patients with acute kidney injury.J Am Soc Nephrol,2006,17:3132-3138.
[16].王质刚.杂合肾脏替代概念及发展前景.中国血液净化.2009,12：639～643.
[17].Kumar VA,Yeun JY,Depner TA,et al.Extended daily dialysis vs.continuous hemodialysis for ICU patients with acute renal failure:a two-year single center report.Int J Artif Organs,2004,27:371～379.
[18].Saudan P,Niederberger M,De Seigneux S,et al.Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure.Kidney Int.2006,70:1312～1317.
[19].Palevsky PM,Zhang JH,O'Connor TZ,et al.VA/NIH Acute Renal Failure Trial Network,Intensity of renal support in critically ill patients with acute kidney injury.N Engl J Med,2008,359:7-20.