过敏毒素C5a在顺铂导致的小鼠肾毒性中的作用
摘要
序言
顺铂是临床常用的广谱、有效的一线抗癌药,对肺癌、睾丸癌、卵巢癌、膀胱癌、头颈部肿瘤等有极好的治疗效果。肾脏毒性是顺铂最主要的副作用。随着用药剂量的增加,顺铂的抗癌作用成倍增加,但同时引起的肾脏毒性也随之成倍加重,临床上大约有三分之一的患者在顺铂治疗后有不同程度的肾功能障碍。肾毒性已经成为提高顺铂使用剂量及其应用范围的主要限制。铂类药物肾毒性的具体分子机制还不完全清楚,一般认为可能与DNA损伤、caspase活化、线粒体功能障碍及自由基形成相关,近来亦有许多发现提示炎症机制在顺铂肾毒性发生中起关键作用。有报道顺铂治疗的患者尿β2-微球蛋白、白蛋白升高的同时,尿液中MAC水平也相应升高,说明铂类药物的肾毒性可能与补体系统的激活有关。本研究探讨了补体系统的激活在顺铂肾脏损伤发生机制中的作用。
材料与方法
健康6～8周龄雄性C5基因敲除小鼠、C5aR基因敲除小鼠、CD59ab基因敲除小鼠及其各自相同基因背景的野生型小鼠给予单次腹腔注射20mg/kg体重的顺铂或者等量的无菌生理盐水,部分C5基因敲除小鼠在注射顺铂前10分钟静脉注射人C5蛋白或C5a蛋白。注射顺铂后72小时处死小鼠取材检测。
结果
顺铂可导致野生型小鼠血肌酐、尿素氮水平明显增高,肾小管上皮细胞凋亡、中性粒细胞浸润,肾组织氧化应激损伤,炎症因子表达。而C5基因敲除小鼠可明显耐受顺铂导致的肾脏损伤。C5蛋白预处理可恢复C5基因敲除小鼠对顺铂的敏感性。在补体激活过程中,C5裂解为C5a和C5b,前者又称为过敏毒素,与C5aR结合发挥生物学效应;后者则形成MAC。为研究C5a缺乏是否为C5基因敲除鼠对顺铂肾毒性耐受的保护因素,我们在应用顺铂前注射C5a,发现C5a也可同样恢复C5基因敲除小鼠对顺铂的敏感性。提示了C5a在顺铂肾毒性中的重要作用。同C5a基因敲除小鼠类似,C5aR基因敲除小鼠也可耐受顺铂肾毒性。C5或C5aR基因敲除小鼠的肾功能指标、肾组织中肾小管上皮细胞的凋亡,中性粒细胞浸润,氧化应激损伤,炎症因子、caspase的表达及p-STAT3 and NF-kB的活化明显较相应的野生型小鼠减轻。有趣的是,CD59基因的敲除并不能缓解顺铂对小鼠的肾脏损害;顺铂诱导形成的MAC沉积在C5aR基因敲除小鼠的肾组织,而不在C5基因敲除鼠的肾组织中。
结论
补体系统激活过程中C5a与C5aR结合,激活其下游信号转导通路,继而引起多种炎症性细胞因子的产生、中性粒细胞的浸润是介导顺铂小鼠肾脏损伤的重要环节;补体激活过程中MAC的形成与顺铂小鼠肾脏损伤无关;阻断C5aR可能减轻顺铂的肾毒性。
Cisplatin is one of the most potent chemotherapeutic agents available that is widely used to treat a variety of malignancies, including ovarian, lung, head, and neck cancers, as well as testicular and bladder tumors. Unfortunately, at high doses, cisplatin induces cumulative and dose-dependent nephrotoxicity, a major side effect that restricts maximization of therapeutic effects. In clinical practice, approximately one third of patients experience renal dysfunction after treatment with cisplatin. Cisplatin nephrotoxicity is likely caused by a combination of multiple mechanisms, involving DNA damage, caspase activation, mitochondrial dysfunction and formation of reactive oxygen species. However, the exact molecular and cellular mechanisms by which cisplatin induces nephrotoxicity remain unclear. Recently, results from multiple studies strongly implicate the importance of inflammatory mechanisms in the pathogenesis of cisplatin-induced nephrotoxicity. Importantly, urinary levels of complement terminal complexes (C5b-9), the final end-product of complement activation, is increased in cisplatin-treated patients and is associated with nephrotoxicity. These findings, coupled with the important role of complements in immune and inflammatory responses, have led us to hypothesize that activation of the complement system contribute to cisplatin-induced nephrotoxicity.
Materials and Methods
Pathogen-free, 6-to 8-week-old male C5-deficient mice (C5KO), C5aR knockout mice (C5aRKO), CD59ab double knockout mice (CD59KO) and corresponding control mice were treated with cisplatin (dissolved in saline, 20μg/g body wt ip) or saline and sacrificed 72 hours post injection. In some groups, C5KO mice were injected with C5 or C5a proteins 10 min before cisplatin administration. Blood was collected immediately on the day of sacrifice for creatinine and blood urea nitrogen assay. The kidneys were either immediately fixed with 4% formaldehyde and 2% glutaraldehyde for histology measurement or snap-frozen and kept at -80℃until molecular biology examination.
Results
Our data showed that cisplatin treatment significantly elevated serum BUN and creatinine levels, increased the percentage of apoptotic tubular cells and renal neutrophil infiltration and oxidative/nitrosative stress in wild-type mice, which were significantly reduced in C5KO mice. Pretreatment with purified C5 restored sensitivity to cisplatin-induced nephrotoxicity in C5KO mice. These results suggested that C5 was an important mediator of increased apoptosis, inflammatory cell infiltration, and oxidative/nitrosative stress observed with cisplatin-induced nephrotoxicity. During complement activation, C5 is cleaved into two smaller fragments, C5a and C5b. The C5b fragment participates in the formation of membrane attack complexes (MACs), while C5a functions as an anaphylatoxin. In order to determine whether C5a was indeed the protective factor in cisplatin-induced renal injury in C5KO mice, C5a was injected to C5KO mice before cisplatin administration. We found injection of C5a also restored cisplatin-induced nephrotoxicity in C5KO mice as well as administration of C5. Furthermore, similar to C5KO mice, C5aRKO mice were also resistant to cisplatin-induced nephrotoxicity. In wild-type mice, administration of cisplatin triggered the increased renal expression of multiple cytokines and caspases. This induction was diminished in C5KO mice, which was restored by pretreatment with C5 or C5a proteins. Moreover, we also demonstrated that C5a or C5aR deficiency diminished cisplatin-induced cytokine and caspase gene expression, as well as p-STAT3 and NF-kB activation in kidneys from mice. Interestingly, renal injury induced by cisplatin was similar between wild-type and CD59KO mice, and the formation of MACs by cisplatin in the kidney was diminished in C5KO mice, but not in C5aRKO mice. Taken together, these findings indicated that C5a contributed to cisplatin-induced nephrotoxicity through a signaling pathway downstream from C5a receptor binding.
Conclusion
In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results. C5aR blockade could be a novel strategy in attenuating cisplatin-induced kidney injury.
顺铂是临床常用的广谱、有效的一线抗癌药,对肺癌、睾丸癌、卵巢癌、膀胱癌、头颈部肿瘤等有极好的治疗效果。肾脏毒性是顺铂最主要的副作用。随着用药剂量的增加,顺铂的抗癌作用成倍增加,但同时引起的肾脏毒性也随之成倍加重,临床上大约有三分之一的患者在顺铂治疗后有不同程度的肾功能障碍。肾毒性已经成为提高顺铂使用剂量及其应用范围的主要限制。铂类药物肾毒性的具体分子机制还不完全清楚,一般认为可能与DNA损伤、caspase活化、线粒体功能障碍及自由基形成相关,近来亦有许多发现提示炎症机制在顺铂肾毒性发生中起关键作用。有报道顺铂治疗的患者尿β2-微球蛋白、白蛋白升高的同时,尿液中MAC水平也相应升高,说明铂类药物的肾毒性可能与补体系统的激活有关。本研究探讨了补体系统的激活在顺铂肾脏损伤发生机制中的作用。
材料与方法
健康6～8周龄雄性C5基因敲除小鼠、C5aR基因敲除小鼠、CD59ab基因敲除小鼠及其各自相同基因背景的野生型小鼠给予单次腹腔注射20mg/kg体重的顺铂或者等量的无菌生理盐水,部分C5基因敲除小鼠在注射顺铂前10分钟静脉注射人C5蛋白或C5a蛋白。注射顺铂后72小时处死小鼠取材检测。
结果
顺铂可导致野生型小鼠血肌酐、尿素氮水平明显增高,肾小管上皮细胞凋亡、中性粒细胞浸润,肾组织氧化应激损伤,炎症因子表达。而C5基因敲除小鼠可明显耐受顺铂导致的肾脏损伤。C5蛋白预处理可恢复C5基因敲除小鼠对顺铂的敏感性。在补体激活过程中,C5裂解为C5a和C5b,前者又称为过敏毒素,与C5aR结合发挥生物学效应;后者则形成MAC。为研究C5a缺乏是否为C5基因敲除鼠对顺铂肾毒性耐受的保护因素,我们在应用顺铂前注射C5a,发现C5a也可同样恢复C5基因敲除小鼠对顺铂的敏感性。提示了C5a在顺铂肾毒性中的重要作用。同C5a基因敲除小鼠类似,C5aR基因敲除小鼠也可耐受顺铂肾毒性。C5或C5aR基因敲除小鼠的肾功能指标、肾组织中肾小管上皮细胞的凋亡,中性粒细胞浸润,氧化应激损伤,炎症因子、caspase的表达及p-STAT3 and NF-kB的活化明显较相应的野生型小鼠减轻。有趣的是,CD59基因的敲除并不能缓解顺铂对小鼠的肾脏损害;顺铂诱导形成的MAC沉积在C5aR基因敲除小鼠的肾组织,而不在C5基因敲除鼠的肾组织中。
结论
补体系统激活过程中C5a与C5aR结合,激活其下游信号转导通路,继而引起多种炎症性细胞因子的产生、中性粒细胞的浸润是介导顺铂小鼠肾脏损伤的重要环节;补体激活过程中MAC的形成与顺铂小鼠肾脏损伤无关;阻断C5aR可能减轻顺铂的肾毒性。
Cisplatin is one of the most potent chemotherapeutic agents available that is widely used to treat a variety of malignancies, including ovarian, lung, head, and neck cancers, as well as testicular and bladder tumors. Unfortunately, at high doses, cisplatin induces cumulative and dose-dependent nephrotoxicity, a major side effect that restricts maximization of therapeutic effects. In clinical practice, approximately one third of patients experience renal dysfunction after treatment with cisplatin. Cisplatin nephrotoxicity is likely caused by a combination of multiple mechanisms, involving DNA damage, caspase activation, mitochondrial dysfunction and formation of reactive oxygen species. However, the exact molecular and cellular mechanisms by which cisplatin induces nephrotoxicity remain unclear. Recently, results from multiple studies strongly implicate the importance of inflammatory mechanisms in the pathogenesis of cisplatin-induced nephrotoxicity. Importantly, urinary levels of complement terminal complexes (C5b-9), the final end-product of complement activation, is increased in cisplatin-treated patients and is associated with nephrotoxicity. These findings, coupled with the important role of complements in immune and inflammatory responses, have led us to hypothesize that activation of the complement system contribute to cisplatin-induced nephrotoxicity.
Materials and Methods
Pathogen-free, 6-to 8-week-old male C5-deficient mice (C5KO), C5aR knockout mice (C5aRKO), CD59ab double knockout mice (CD59KO) and corresponding control mice were treated with cisplatin (dissolved in saline, 20μg/g body wt ip) or saline and sacrificed 72 hours post injection. In some groups, C5KO mice were injected with C5 or C5a proteins 10 min before cisplatin administration. Blood was collected immediately on the day of sacrifice for creatinine and blood urea nitrogen assay. The kidneys were either immediately fixed with 4% formaldehyde and 2% glutaraldehyde for histology measurement or snap-frozen and kept at -80℃until molecular biology examination.
Results
Our data showed that cisplatin treatment significantly elevated serum BUN and creatinine levels, increased the percentage of apoptotic tubular cells and renal neutrophil infiltration and oxidative/nitrosative stress in wild-type mice, which were significantly reduced in C5KO mice. Pretreatment with purified C5 restored sensitivity to cisplatin-induced nephrotoxicity in C5KO mice. These results suggested that C5 was an important mediator of increased apoptosis, inflammatory cell infiltration, and oxidative/nitrosative stress observed with cisplatin-induced nephrotoxicity. During complement activation, C5 is cleaved into two smaller fragments, C5a and C5b. The C5b fragment participates in the formation of membrane attack complexes (MACs), while C5a functions as an anaphylatoxin. In order to determine whether C5a was indeed the protective factor in cisplatin-induced renal injury in C5KO mice, C5a was injected to C5KO mice before cisplatin administration. We found injection of C5a also restored cisplatin-induced nephrotoxicity in C5KO mice as well as administration of C5. Furthermore, similar to C5KO mice, C5aRKO mice were also resistant to cisplatin-induced nephrotoxicity. In wild-type mice, administration of cisplatin triggered the increased renal expression of multiple cytokines and caspases. This induction was diminished in C5KO mice, which was restored by pretreatment with C5 or C5a proteins. Moreover, we also demonstrated that C5a or C5aR deficiency diminished cisplatin-induced cytokine and caspase gene expression, as well as p-STAT3 and NF-kB activation in kidneys from mice. Interestingly, renal injury induced by cisplatin was similar between wild-type and CD59KO mice, and the formation of MACs by cisplatin in the kidney was diminished in C5KO mice, but not in C5aRKO mice. Taken together, these findings indicated that C5a contributed to cisplatin-induced nephrotoxicity through a signaling pathway downstream from C5a receptor binding.
Conclusion
In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results. C5aR blockade could be a novel strategy in attenuating cisplatin-induced kidney injury.
引文
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1.Rosenberg B,VanCamp L,Trosko JE,et al.Platinum compounds:a new class of potent antitumour agents.Nature.1969;222(5191):385-6.
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8.Galanski M.Recent developments in the field of anticancer platinum complexes.Recent Patents Anticancer Drug Discov.2006;1(2):285-95.
9.Ries F,Klastersky J.Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity.Am J Kidney Dis.1986;8(5):368 79.
10.Lebwohl D,Canetta R.Clinical development of platinum complexes in cancer therapy:an historical perspective and an update.Eur J Cancer.1998;34(10):1522-34.
11.Gore ME,Calvert AH,Smith LE.High dose carboplatin in the treatment of lung cancer and mesothelioma:a phase I dose escalation study.Eur J Cancer Clin Oncol.1987;23(9):1391-7.
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11.Gore ME,Calvert AH,Smith LE.High dose carboplatin in the treatment of lung cancer and mesothelioma:a phase I dose escalation study.Eur J Cancer Clin Oncol.1987;23(9):1391-7.
12.Taguchi T,Nazneen A,Abid MR,et al.Cisplatin-associated nephrotoxicity and pathological events.Contrib Nephrol.2005;148:107-21.
13.Megyesi J,Safirstein RL,Price PM.Induction of p21WAFl/CIPl/SDIl in kidney tubule cells affects the course of cisplatin-induced acute renal failure.J Clin Invest.1998 Feb 15;101(4):777-82.
14.Faubel S,Ljubanovic D,Reznikov L,Somerset H,Dinarello CA,Edelstein CL.Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis.Kidney Int.2004;66(6):2202-13.
15.Taguchi T,Nazneen A,Abid MR,et al.Cisplatin-associated nephrotoxicity and pathological events.Contrib Nephrol.2005;148:107-21.
16.Matsushima H,Yonemura K,Ohishi K,Hishida A.The role of oxygen free radicals in cisplatin-induced acute renal failure in rats.J Lab Clin Med.1998 Jun;131(6):518-26.
17.Kawai Y,Nakao T,Kunimura N,Kohda Y,Gemba M.Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury.J Pharmacol Sci.2006;100(1):65-72.
18.Liu M,Chien CC,Burne-Taney M,Molls RR,Racusen LC,Colvin RB,Rabb H.A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity.J Am Soc Nephrol.2006;17(3):765-74.
19.Cetin R,Devrim E,Kilicoglu B,et al.Cisplatin impairs antioxidant system and causes oxidation in rat kidney tissues:possible protective roles of natural antioxidant foods.J Appl Toxicol.2006;26(l):42-6.
20.Kim SH,Hong KO,Hwang JK,et al.Xanthorrhizol has a potential to attenuate the high dose cisplatin-induced nephrotoxicity in mice.Food Chem Toxicol.2005;43(1):117-22.
21.Atessahin A,Yilmaz S,Karahan I,et al.Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats.Toxicology.2005;212(2-3):116-23.
22.Shimeda Y,Hirotani Y,Akimoto Y,et al.Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats.Biol Pharm Bull.2005;28(9):1635-8.
23.Kadikoylu G,Bolaman Z,Demir S,et al.The effects of desferrioxamine on cisplatin-induced lipid peroxidation and the activities of antioxidant enzymes in rat kidneys.Hum Exp Toxicol.2004;23(1):29-34.
24.Naziroglu M,Karaoglu A,Aksoy AO.Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal,liver and lens tissues in rats.Toxicology.2004;195(2-3):221-30.
25.Mora Lde O,Antunes LM,Francescato HD,et al.The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats.Pharmacol Res.2003;47(6):517-22.
26.Ozen S,Akyol O,Iraz M,et al.Role of caffeic acid phenethyl ester,an active component of propolis,against cisplatin-induced nephrotoxicity in rats.J Appl Toxicol.2004;24(1):27-35.
27.Pan H,Mukhopadhyay P,Rajesh M,et al.Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress,inflammation,and cell death.J Pharmacol Exp Ther.2009;328(3):708-14.
28.Satoh M,Kashihara N,Fujimoto S,et al.A novel free radical scavenger,edarabone,protects against cisplatin-induced acute renal damage in vitro and in vivo.J Pharmacol Exp Ther.2003;305(3):1183-90.
29.Hsu DZ,Chen KT,Lin TH,et al.Sesame oil attenuates Cisplatin-induced hepatic and renal injuries by inhibiting nitric oxide-associated lipid peroxidation in mice.Shock.2007;27(2):199-204.
30.Lee S,Moon SO,Kim W,et al.Protective role of L-2-oxothiazolidine-4-carboxylic acid in cisplatin-induced renal injury.Nephrol Dial Transplant.2006;21(8):2085-95.
31.Aydinoz S,Uzun G,Cermik H,et al.Effects of different doses of hyperbaric oxygen on cisplatin-induced nephrotoxicity.Ren Fail.2007;29(3):257-63.
32.Ajith TA,Jose N,Janardhanan KK.Amelioration of cisplatin induced nephrotoxicity in mice by ethyl acetate extract of a polypore fungus,Phellinus rimosus.J Exp Clin Cancer Res.2002;21(2):213-7.
33.Badary OA,Abdel-Maksoud S,Ahmed WA,et al.Naringenin attenuates cisplatin nephrotoxicity in rats.Life Sci.2005;76(18):2125-35.
34.Weijl NI,Elsendoorn TJ,Lentjes EG,et al.Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy:a randomised,double-blind,placebo-controlled study.Eur J Cancer.2004;40(11):1713-23.
35.Pace A,Savarese A,Picardo M,et al.Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy.J Clin Oncol.2003;21(5):927-31.
36.Passauer J,Pistrosch F,B (?) ssemaker E.Nitric oxide in chronic renal failure.Kidney Int.2005;67(5):1665-7.
37.Saad SY,Najjar TA,Daba MH,et al.Inhibition of nitric oxide synthase aggravates cisplatin-induced nephrotoxicity:effect of 2-amino-4-methylpyridine.Chemotherapy.2002;48(6):309-15.
38.Saleh S,El-Demerdash E.Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity:role of nitric oxide.Basic Clin Pharmacol Toxicol.2005;97(2):91-7.
39.Santoso JT,Lucci JA 3rd,Coleman RL,et al.Saline,mannitol,and furosemide hydration in acute cisplatin nephrotoxicity:a randomized trial.Cancer Chemother Pharmacol.2003;52(1):13-8.
40.Hanigan MH,Deng M,Zhang L,et al.Stress response inhibits the nephrotoxicity of cisplatin.Am J Physiol Renal Physiol.2005;288(1):F125-32.
41.Fenoglio C,Boicelli CA,Ottone M,et al.Protective effect of procaine hydrochloride on cisplatin-induced alterations in rat kidney.Anticancer Drugs.2002;13(10):1043-54.
42.Viale M,Vannozzi MO,Pastrone I,et al.Reduction of cisplatin nephrotoxicity by procainamide:does the formation of a cisplatin-procainamide complex play a role?J Pharmacol Exp Then 2000;293(3):829-36.
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