中国医科大学学报

中国医科大学学报
  • 中文核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
  • BA、CA收录

中国医科大学学报 ›› 2018, Vol. 47 ›› Issue (1): 1-5.doi: 10.12007/j.issn.0258-4646.2018.01.001

• 论著 •    下一篇

Rho激酶抑制剂通过抑制Toll样受体4和核因子κB信号通路缓解脂多糖诱导的肾损伤

丁仁彧, 肇冬梅, 胡紫薇, 王亮, 李鑫, 孙旖旎, 章志丹, 马晓春   

  1. 中国医科大学附属第一医院重症医学科, 沈阳 110001
  • 收稿日期:2017-04-28 出版日期:2018-01-30 发布日期:2017-12-23
  • 通讯作者: 马晓春 E-mail:xcma2972@sina.com
  • 作者简介:丁仁彧(1980-),男,副教授,博士.
  • 基金资助:
    国家自然科学基金青年项目(81201484);辽宁省自然科学基金(201602819)

Rho-kinase Inhibitor Ameliorates Lipopolysaccharide-induced Kidney Injury by Inhibiting Toll-like Receptor 4 and Nuclear Factor-κB Signaling Pathway

DING Renyu, ZHAO Dongmei, HU Ziwei, WANG Liang, LI Xin, SUN Yini, ZHANG Zhidan, MA Xiaochun   

  1. Department of Intensive Care Unit, The First Hospital, China Medical University, Shenyang 110001, China
  • Received:2017-04-28 Online:2018-01-30 Published:2017-12-23

摘要: 目的 探讨Rho激酶抑制剂对内毒素血症小鼠肾损伤的影响及其分子生物学机制。方法 将成年雄性C57BL/6小鼠随机分成对照组、脂多糖(LPS)组、LPS+Y-27632组,每组8只。采用LPS(30 mg/kg)腹腔内注射建立内毒素血症小鼠模型。造模前18 h和1 h分别予以Rho激酶特异性抑制剂Y-27632或等量生理盐水腹腔注射,造模后8 h处死小鼠,留取血清及肾组织做进一步分析。结果 Rho激酶抑制剂Y-27632预处理明显减轻了LPS诱导的急性肾损伤;Y-27632能够显著降低内毒素血症小鼠肾脏炎性细胞因子(肿瘤坏死因子α和白细胞介素1β)的表达,抑制肾脏caspase-3蛋白的表达;Y-27632预处理显著下调内毒素血症小鼠肾脏Toll样受体4(TLR4)蛋白表达及核因子κB(NF-κB) p65磷酸化水平。结论 Rho激酶抑制剂可能通过抑制TLR4和NF-κB信号通路降低内毒素血症小鼠肾脏的炎症反应,缓解LPS诱导的急性肾损伤。

关键词: Rho激酶, 脂多糖, 肾损伤, Toll样受体4, 核因子κB

Abstract: Objective To explore whether Rho kinase inhibitor protects endotoxemia mice from kidney injury,and to investigate the mechanism underlying this effect. Methods Adult male C57BL/6 mice were randomly divided into three groups (n=8 for each group):control,lipopolysaccharide (LPS),and LPS+ Y-27632 (Rho kinase inhibitor). For induction of acute kidney injury,mice were administered 30 mg/kg LPS intraperitoneally. Y-27632 (10 mg/kg body weight) was injected intraperitoneally 18 h and 1 h before injection of LPS,and an equal volume of sterile saline was administered at the corresponding time point in each group. The mice were killed 8 h after LPS administration. Blood samples and kidney tissues were taken and preserved for subsequent analysis. Results Pretreatment with Y-27632 significantly attenuated LPS-induced kidney injury;pretreatment with Y-27632 markedly reduced renal expression of inflammatory cytokines (TNF-α and IL-1β) in endotoxemia mouse,and also significantly inhibited LPS-induced caspase-3 expression in the kidney;and Y-27632 pretreatment dramatically reduced TLR4 protein expression and NF-κBp65 phosphorylation in kidney tissues of endotoxemia mouse. Conclusion Rho kinase inhibitor may inhibit TLR4 and NF-κB signaling pathway to reduce the inflammatory response in the kidneys of endotoxemia mice and alleviate acute renal injury induced by LPS.

Key words: Rho kinase, lipopolysaccharide, acute kidney injury, Toll-like receptor 4, nuclear factor-κB

中图分类号: 

  • R692.5
[1] SUH SH,KIM CS,CHOI JS,et al. Acute kidney injury in patients with sepsis and septic shock:risk factors and clinical outcomes[J]. Yonsei Med J,2013,54(4):965-972. DOI:10.3349/ymj.2013.54.4.965.
[2] LAFRANCE JP,MILLER DR. Acute kidney injury associates with increased long-term mortality[J]. J Am Soc Nephrol,2010,21(2):345-352. DOI:10.1681/ASN.2009060636.
[3] ZARJOU A,AGARWAL A. Sepsis and acute kidney injury[J]. J Am Soc Nephrol,2011,22(6):999-1006. DOI:10.1681/ASN. 2010050484.
[4] MATEJOVIC M,CHVOJKA J,RADEJ J,et al. Sepsis and acute kidney injury are bidirectional[J]. Contrib Nephrol,2011,174:78-88. DOI:10.1159/000329239.
[5] GUPTA A,RHODES GJ,BERG DT,et al. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2[J]. Am J Physiol Renal Physiol,2007,293(1):F245-F254. DOI:10.1152/ajprenal.00477.2006.
[6] DOI K,LEELAHAVANICHKUL A,YUEN PS,et al. Animal models of sepsis and sepsis-induced kidney injury[J]. J Clin Invest,2009,119(10):2868-2878. DOI:10.1172/JCI39421.
[7] RAMESH G,REEVES WB. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity[J]. J Clin Invest,2002,110(6):835-842. DOI:10.1172/JCI15606.
[8] RIENTO K,RIDLEY AJ. Rocks:multifunctional kinases in cell behaviour[J]. Nat Rev Mol Cell Biol,2003,4(6):446-456. DOI:10.1038/nrm1128.
[9] BOKOCH GM. Regulation of innate immunity by Rho GTPases[J]. Trends Cell Biol,2005,15(3):163-171. DOI:10.1016/j.tcb.2005. 01.002.
[10] DING RY,ZHAO DM,ZHANG ZD,et al. Pretreatment of Rho kinase inhibitor inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in mice[J]. J Surg Res,2011,171(2):e209-e214. DOI:10.1016/j.jss.2011.08.009.
[11] CUNNINGHAM PN,DYANOV HM,PARK P,et al. Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney[J]. J Immunol,2002,168(11):5817-5823.
[12] PATEL NS,CHATTERJEE PK,DI PAOLA R,et al. Endogenous interleukin-6 enhances the renal injury,dysfunction,and inflammation caused by ischemia/reperfusion[J]. J Pharmacol Exp Ther,2005,312(3):1170-1178. DOI:10.1124/jpet.104.078659.
[13] FAGGIONI R,FANTUZZI G,FULLER J,et al. IL-1 beta mediates leptin induction during inflammation[J]. Am J Physiol,1998,274(1 Pt 2):R204-R208.
[14] XU C,CHANG A,HACK BK,et al. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis[J]. Kidney Int,2014,85(1):72-81. DOI:10.1038/ki.2013.286.
[15] PALANI K,RAHMAN M,HASAN Z,et al. Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils inabdominal sepsis[J]. Eur J Pharmacol,2012,682(1/3):181-187. DOI:10.1016/j.ejphar.2012.02.022.
[16] HASAN Z,PALANI K,RAHMAN M,et al. Rho-kinase signaling regulates pulmonary infiltration of neutrophils in abdominal sepsis via attenuation of CXC chemokine formation and Mac-1 expression on neutrophils[J]. Shock,2012,37(3):282-288. DOI:10.1097/SHK.0b013e3182426be4.
[17] HASAN Z,PALANI K,ZHANG S,et al. Rho kinase regulates induction of T-cell immune dysfunction in abdominal sepsis[J]. Infect Immun,2013,81(7):2499-2506. DOI:10.1128/IAI.00126-13.
[18] CHAO W. Toll-like receptor signaling:a critical modulator of cell survival and ischemic injury in the heart[J]. Am J Physiol Heart Circ Physiol,2009,296(1):H1-H12. DOI:10.1152/ajpheart.00995.2008.
[19] KHAKPOUR S,WILHELMSEN K,HELLMAN J. Vascular endothelial cell Toll-like receptor pathways in sepsis[J]. Innate Immun,2015,21(8):827-846. DOI:10.1177/1753425915606525.
[20] SAVVA A,ROGER T. Targeting toll-like receptors:promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases[J]. Front Immunol,2013,4:387. DOI:10.3389/fimmu.2013.00387.
[21] CARMODY RJ,CHEN YH. Nuclear factor-kappaB:activation and regulation during toll-like receptor signaling[J]. Cell Mol Immunol,2007,4(1):31-41.
[22] KAWAI T,AKIRA S. Signaling to NF-kappaB by Toll-like receptors[J]. Trends Mol Med,2007,13(11):460-469. DOI:10.1016/j.molmed.2007.09.002.
[23] CUNNINGHAM PN,WANG Y,GUO R,et al. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure[J]. J Immunol,2004,172(4):2629-2635.
[24] ZHANG B,RAMESH G,UEMATSU S,et al. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity[J]. J Am Soc Nephrol,2008,19(5):923-932. DOI:10.1681/ASN.2007090982.
[25] SANZ AB,SANCHEZ-NINO MD,RAMOS AM,et al. NF-κB in renal inflammation[J]. J Am Soc Nephrol,2010,21(8):1254-1262. DOI:10.1681/ASN.2010020218.
[26] CHUNZHI G,ZUNFENG L,CHENGWEI Q,et al. Hyperin protects against LPS-induced acute kidney injury by inhibiting TLR4 and NLRP3 signaling pathways[J]. Oncotarget,2016,7(50):82602-82608. DOI:10.18632/oncotarget.13010.
[1] 邢海会, 丁晓慧, 解辉, 王忠华, 谢菊华, 陈丰洋, 罗崟洲, 周胜男. Toll样受体4对大鼠脑缺血再灌注损伤的作用[J]. 中国医科大学学报, 2018, 47(3): 206-211.
[2] 杜国强, 王立银, 王晓凤, 李君, 张明明, 王瑾. APE1通过NF-κB通路调节PD-L1在喉鳞状细胞癌中的表达[J]. 中国医科大学学报, 2018, 47(10): 865-870.
[3] 曾仁庆 ,吴曦子 ,赵洋子 ,邓云蕾 ,于诗源 ,李蕙伊 ,刘畅 ,范晨玲 ,王红 ,崇巍. 丙戊酸对百草枯与脂多糖诱导的巨噬细胞炎性极化的作用[J]. 中国医科大学学报, 2017, 46(6): 548-551.
[4] 宋宏伟,杨琛,刘伟,刘志. 白细胞介素 17A 在急性百草枯中毒小鼠肾损伤中的作用[J]. 中国医科大学学报, 2017, 46(5): 392-396.
[5] 黄菁,郑美玲,王玉珏,于庭. 尿肾损伤分子1、血清胱抑素C和尿中性粒细胞明胶酶相关性脂质运载蛋白预测子痫前期发病和早期肾损伤的价值[J]. 中国医科大学学报, 2016, 45(5): 460-463.
[6] 李国福,赵阳,朱孟杰,秦含玉,臧彬. α硫辛酸后处理对脓毒症大鼠急性肾损伤的影响及机制[J]. 中国医科大学学报, 2015, 44(7): 577-580.
[7] 吴晓黎,王智敏,郝颖,梁鹤缤,郑东明,郭阳. 姜黄素对糖尿病大鼠血脑屏障的影响[J]. 中国医科大学学报, 2015, 44(4): 298-301.
[8] 于霏,金元哲,雷明明,张学颖,张晓春,刘君. FKN、PI3K及NF?κB对人外周血单个核细胞IL?6表达的影响及缬沙坦的干预作用[J]. 中国医科大学学报, 2015, 44(3): 214-216.
[9] 董雪松, 王蕊, 许小扬, 刘伟, 孙大壮, 刘志. 百草枯致小鼠心肌损伤中Toll样受体4表达及意义[J]. 中国医科大学学报, 2015, 44(10): 891-896.
[10] 吴荣,马天馨,曾越灿. 血管紧张素Ⅱ1型受体拮抗剂在大鼠放射性心脏损伤中保护作用的研究[J]. 中国医科大学学报, 2015, 44(1): 20-26.
[11] 张振勇,曹秋婷,吴荣. 放射性肺损伤中核因子κB和细胞间黏附分子1的表达及意义[J]. 中国医科大学学报, 2014, 43(2): 155-158.
[12] 范愈燕,孙永新,吕翠岩,张越颍,李平,西山成,支楠. 内毒素对人的类糜蛋白转基因小鼠生存率及组织内类糜蛋白酶活性的影响[J]. 中国医科大学学报, 2014, 43(12): 1071-1074.
[13] 王雪梅,尚德浩,潘亚萍. 姜黄素对脂多糖刺激成骨细胞骨吸收的影响[J]. 中国医科大学学报, 2014, 43(11): 982-985.
[14] 侯玲,杜悦,郭金杰,吴玉斌,赵成广. 血清和尿中NGAL、KIM-1水平在儿童泌尿系统疾病致急性肾损伤诊断中的作用[J]. 中国医科大学学报, 2013, 42(7): 619-522.
[15] 刘玲,刘新伟,梁灿鑫,何东伟,俞莹,王萍. 白藜芦醇对脂多糖诱导的H9c2心肌细胞损伤的影响[J]. 中国医科大学学报, 2013, 42(4): 339-343.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!

中国医科大学学报版权所有©2018

未经允许,严禁擅自转载本站图文资料

地址:中国 沈阳市沈北新区蒲河路77号 110122

辽ICP备05014850

JOURNAL OF CHINA MEDICAL UNIVERSITY

ADDRESS: NO.77 PUHE ROAD

SHENYANG NORTH NEW AREA, SHENYANG

LIAONING PROVINCE, P.R. CHINA