MicroRNA-29在肾纤维化进程中的研究进展

doi:10.16098/j.issn.0529-1356.2017.05.022

摘要/Abstract

摘要：

肾纤维化是慢性肾脏疾病(CKD)发展到终末期肾衰竭的共同病理，主要表现为细胞外基质(ECM)的过度沉积。MicroRNAs(miRNAs)是一类微小非编码RNAs，通过抑制目的基因mRNAs转录后的表达而调控肾脏的生理功能及稳态。miR-29s通过调节ECM的合成与沉积以及上皮-间质转化（EMT）发挥抗纤维化作用，另外，miR-29s与多种炎症和促纤维化通路相互作用，其作为治疗肾纤维化的试剂或者靶点研究有着重要意义和广泛前景。本文中我们综述了最近有关miR-29s抗肾纤维化作用的研究成果。

关键词: 细胞外基质, 上皮细胞-间充质转化, miRNA-29, 肾纤维化

Abstract:

One of the histopathological features of Chronic kidney disease (CKD) is renal fibrosis which is accompanied by the deposition of extracellular matrix (ECM). MicroRNAs are short non-coding RNAs that regulate most of important processes about renal physiological functions and homeostatsis. miR-29s are involved in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial-mesenchymal transition (EMT). In this review, we describe interactions of miR-29s with multiple pro-fibrotic and inflammatory pathways and miR-vs as a promising therapeutic reagent or target for the treatment of renal fibrosis. We also review the mechanism of microRNA-29s associated with renal fibrosis.

Key words: Extracellular matrix, Epithelial-mesenchymal transition, miRNA-29, Renal fibrosis

刘祎孙雪娇李城王曦廷李彧. MicroRNA-29在肾纤维化进程中的研究进展[J]. 解剖学报, 2017, 48(5): 622-627.

LIU Yi SUN Xue-jiao LI Cheng WANG Xi-ting LI Yu. Advances in the roles of microRNA-29 in renal fibrosis[J]. Acta Anatomica Sinica, 2017, 48(5): 622-627.

参考文献

［1］Kriegel AJ, Liu Y, Fang Y, et al. The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury［J］. Physiol Genomics, 2012,44(4):237-244.

［2］van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis［J］. Proc Natl Acad Sci U S A, 2008,105(35):13027-13032.

［3］Qin W, Chung AC, Huang XR, et al. TGF-beta/Smad3 signaling promotes renal fibrosis by inhibiting miR-29［J］. J Am Soc Nephrol, 2011,22(8):1462-1474.

［4］Xiao J, Meng XM, Huang XR, et al. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice［J］. Mol Ther, 2012,20(6):1251-1260.

［5］Zhang Y, Huang XR, Wei LH, et al. miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-beta/Smad3 signaling［J］. Mol Ther, 2014,22(5):974-985.

［6］Wang B, Komers R, Carew R, et al. Suppression of microRNA-29 expression by TGF-beta1 promotes collagen expression and renal fibrosis［J］. J Am Soc Nephrol, 2012,23(2):252-265.

［7］Amiel J, de Pontual L, Henrion-Caude A. miRNA, development and disease［J］. Adv Genet, 2012,80:1-36.

［8］Bao X, Zhu X, Liao B, et al. MicroRNAs in somatic cell reprogramming［J］. Curr Opin Cell Biol, 2013,25(2):208-214.

［9］Goljanek-Whysall K, Sweetman D, Münsterberg AE. microRNAs in skeletal muscle differentiation and disease［J］. Clin Sci(Lond), 2012,123(11):611-625.

［10］Cullen BR. MicroRNAs as mediators of viral evasion of the immune system［J］. Nat Immunol, 2013,14(3):205-210.

［11］Chang TC, Yu D, Lee YS, et al. Widespread microRNA repression by Myc contributes to tumorigenesis［J］. Nat Genet, 2008,40(1):43-50.

［12］Mott JL, Kurita S, Cazanave SC, et al. Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-kappaB［J］. J Cell Biochem, 2010,110(5):1155-1164.

［13］Wang H, Garzon R, Sun H, et al. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma［J］. Cancer Cell, 2008,14(5):369-381.

［14］Kapinas K, Kessler C, Ricks T, et al. miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop［J］. J Biol Chem, 2010,285(33):25221-25231.

［15］Eyholzer M, Schmid S, Wilkens L, et al. The tumour-suppressive miR-29a/b1 cluster is regulated by CEBPA and blocked in human AML［J］. Br J Cancer, 2010,103(2):275-284.

［16］Lan HY. Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation［J］. Int J Biol Sci, 2011,7(7):1056-1067.

［17］Zhou L, Wang L, Lu L, et al. Inhibition of miR-29 by TGF-beta-Smad3 signaling through dual mechanisms promotes transdifferentiation of mouse myoblasts into myofibroblasts［J］. PLoS One, 2012,7(3):e33766.

［18］Jiang L, Zhou Y, Xiong M, et al. Sp1 mediates microRNA-29c-regulated type I collagen production in renal tubular epithelial cells［J］. Exp Cell Res, 2013,319(14):2254-2265.

［19］Ramdas V, McBride M, Denby L, et al. Canonical transforming growth factor-beta signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29［J］. Am J Pathol, 2013,183(6):1885-1896.

［20］Zhang Y, Wang JH, Zhang YY, et al. Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFbeta1 and miR-29 pathways［J］. Sci Rep, 2016,6:23010.

［21］Du B, Ma LM, Huang MB, et al. High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells［J］. FEBS Lett, 2010,584(4):811-816.

［22］Hsu Y, Chang P, Ho C, et al. Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/β-catenin signaling［J］. Scientific Reports, 2016,6:30575.

［23］Cushing L, Kuang P, Lü J. The role of miR-29 in pulmonary fibrosis1［J］. Biochem Cell Biol, 2015,93(2):109-118.

［24］Li Z, Hassan MQ, Jafferji M, et al. Biological functions of miR-29b contribute to positive regulation of osteoblast differentiation［J］. J Biol Chem, 2009,284(23):15676-15684.

［25］Sengupta S, den Boon JA, Chen IH, et al. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins［J］. Proc Natl Acad Sci U S A, 2008,105(15):5874-5878.

［26］Liu Y, Taylor NE, Lu L, et al. Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes［J］. Hypertension, 2010,55(4):974-982.

［27] Ogawa T, Iizuka M, Sekiya Y, et al. Suppression of type I collagen production by microRNA-29b in cultured human stellate cells［J］. Biochem Biophys Res Commun, 2010,391(1):316-321.

［28］Cushing L, Kuang PP, Qian J, et al. miR-29 is a major regulator of genes associated with pulmonary fibrosis［J］. Ame J Respir Cell Mol Biol, 2011,45(2):287-294.

［29］Fang Y, Yu X, Liu Y, et al. miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-alpha activation［J］. Am J Physiol Renal Physiol, 2013,304(10):F1274-F1282.

［30] Roderburg C, Urban G, Bettermann K, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis ［J］? Hepatology, 2011,53(1):209-218.

［31］Maurer B, Stanczyk J, Jüngel A, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis［J］. Arthritis Rheum, 2010,62(6):1733-1743.

［32］Cushing L, Kuang PP, Qian J, et al. miR-29 Is a major regulator of genes associated with pulmonary fibrosis［J］. Am J Respir Cell Mol Biol, 2011,45(2):287-294.

［33] Kantharidis P, Wang B, Carew RM, et al. Diabetes complications: the microRNA perspective［J］. Diabetes, 2011,60(7):1832-1837.

［34］Zhou L, Xu DY, Sha WG, et al. High glucose induces renal tubular epithelial injury via Sirt1/NF-kappaB/microR-29/Keap1 signal pathway［J］. J Transl Med, 2015,13:352.

［35］Meng XM, Tang PM, Li J, et al. TGF-beta/Smad signaling in renal fibrosis［J］. Front Physiol, 2015,6:82.

［36］Chung A C, Dong Y, Yang W, et al. Smad7 suppresses renal fibrosis via altering expression of TGF-beta/Smad3-regulated microRNAs［J］. Mol Ther, 2013,21(2):388-398.

［37］Wang G, Kwan BC, Lai FM, et al. Urinary miR-21, miR-29, and miR-93: novel biomarkers of fibrosis［J］. Am J Nephrol, 2012,36(5):412-418.

［38］de Haan JB. Nrf2 activators as attractive therapeutics for diabetic nephropathy［J］. Diabetes, 2011,60(11):2683-2684.

［39］Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver ［J］ ? Hepatology, 2009,50(6):2007-2013.

［40］Guarino M, Tosoni A, Nebuloni M. Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition［J］. Hum Pathol, 2009,40(40):1365-1376.

［41］Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions［J］. J Clin Invest, 2009,119(6):1429-1437.

［42］Smith BN, Bhowmick NA. Role of EMT in Metastasis and Therapy Resistance［J］. J Clin Med, 2016,5(2). pii: E17.

［43］Cho MH. Renal fibrosis［J］. Korean J Pediatri, 2010,53(7):735-740.

［44］Guo HL, Liao XH, Liu Q, et al. Angiotensin II type 2 receptor decreases transforming growth factor-beta type II receptor expression and function in human renal proximal tubule cells［J］. PLoS One, 2016,11(2):e148696.

［45］Yang DY, Huang XY, Shao JY,et al. The role of microRNA-29b in epithelial-mesenchymal transition of renal tubular epithelial cells induced by angiotensin II［J］. Journal of Wenzhou Medical College, 2013(02):71-77.（in Chinese）

杨德业, 黄晓燕, 邵驾宇, 等. microRNA-29b在血管紧张素Ⅱ诱导肾小管上皮细胞转分化中的作用［J］. 温州医学院学报, 2013(02):71-77.

［46］Xiong YJ, Hu ZhH, Qiu F, et al. MiR-29 down-regulates the expression of several genes involved in the AKT signal pathway［J］. Chinese Journal of Clinicians(Electronic Edition), 2012(14):3871-3874.（in Chinese）

熊玉娟,胡朝晖,邱峰,等. miR-29下调AKT信号通路中多个基因的表达［J］. 中华临床医师杂志(电子版), 2012(14):3871-3874.

［47］Yu H, Shi MJ, Xiao Y, et al. Up- regulation of Snail1 expression in renal tubular epithelial cells through Akt /GSK-3β pathway under high-glucose condition［J］. Chinese Journal of Pathophysiology, 2012(12):2222-2226.（in Chinese）

余红, 石明隽, 肖瑛, 等. Akt/GSK-3β介导高糖上调肾小管上皮细胞Snail1的表达［J］. 中国病理生理杂志, 2012(12):2222-2226.

［48] Pichaiwong W, Hudkins KL, Wietecha T, et al. Reversibility of structural and functional damage in a model of advanced diabetic nephropathy［J］. J Am Soc Nephrol, 2013,24(7):1088-1102.

［49］Lin CL, Lee PH, Hsu YC, et al. MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction［J］. J Am Soc Nephrol, 2014,25(8):1698-1709.

［50］Long J, Wang Y, Wang W, et al. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy［J］. J Biol Chem, 2011,286(13):11837-11848.

［51］Yuen DA, Stead BE, Zhang Y, et al. eNOS deficiency predisposes podocytes to injury in diabetes［J］. J Am Soc Nephrol, 2012,23(11):1810-1823.

［52］Chen HY, Zhong X, Huang XR, et al. MicroRNA-29b inhibits diabetic nephropathy in db/db mice［J］. Mol Ther, 2014,22(4):842-853.

［53］Lü LL, Cao YH, Ni HF, et al. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis［J］. Am J Physiol Renal Physiol, 2013,305(8):F1220-F1227.

［54］Peng H, Zhong M, Zhao W, et al. Urinary miR-29 correlates with albuminuria and carotid intima-media thickness in type 2 diabetes patients［J］. PLoS One, 2013,8(12):e82607.

［55］Mizuno H, Nakamura A, Aoki Y, et al. Identification of muscle-specific microRNAs in serum of muscular dystrophy animal models: promising novel blood-based markers for muscular dystrophy［J］. PLoS One, 2011,6(3):e18388.

［56］Chen X, Chen X, Han Sh, et al. Study on establishment of a real-time fluorescence quantitative PCＲ technique for detecting miR-29a in serum and its clinical primary application ［J］．Journal of Clinical and Experimental Medicine, 2016(1):16-19.（in Chinese）

陈鑫, 陈曦, 韩霜, 等. 血清标本检测miR-29a实时荧光定量PCR方法的建立及临床初步应用［J］. 临床和实验医学杂志, 2016(1):16-19.

［57］Yang F, Li P, Li H, et al. microRNA-29b Mediates the Antifibrotic Effect of Tanshinone IIA in Postinfarct Cardiac Remodeling［J］. J Cardiovasc Pharmacol, 2015,65(5):456-464.

［58］Zheng J, Wu C, Lin Z, et al. Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation—a novel mechanism suppressing liver fibrosis［J］. FEBS J, 2014,281(1):88-103.

[1]	赵宇范军柏树令. 人体脱细胞脂肪组织的制备及组织学评价[J]. 解剖学报, 2020, 51(1): 128-131.
[2]	翁杰黄涛涛王志翊陈婵万新龙周小明梅劲王志斌. 甲状腺脱细胞生物支架的制备及鉴定[J]. 解剖学报, 2019, 50(6): 827-830.
[3]	徐新伟杨玉玲孙志亮张国新曾国栋李洪利尹崇高*. Raptor通过Wnt3a/β-catenin信号通路对乳腺癌侵袭与转移的作用[J]. 解剖学报, 2017, 48(6): 682-687.
[4]	秦雨萌周涛张璐刘裕王新旺王志斌梅劲陈胜华. 大鼠单叶肝去细胞生物支架的制备与鉴定[J]. 解剖学报, 2017, 48(4): 477-481.
[5]	袁莉刚张勇李聪成旭东路琪中. 高原地区藏绵羊与小尾寒羊睾丸细胞外基质组织分布特征比较[J]. 解剖学报, 2017, 48(2): 179-186.
[6]	王鑫高俊玲* 赵曼曼朱会兴田艳霞李冉江小华于雷田景瑞崔建忠. 骨髓间充质干细胞抑制转化生长因子-β1诱导的肺泡Ⅱ型上皮细胞间质化[J]. 解剖学报, 2016, 47(6): 756-762.
[7]	李文春* 李静张红梅王汉琴. 猪胆总管脱细胞支架的制备及组织学评价[J]. 解剖学报, 2015, 46(5): 694-698.
[8]	邵营宽严夏霖饶志恒黄高建李嘉威黄俊杰梅劲* 林刻智*. 大鼠胰腺去细胞天然支架生物相容性的鉴定[J]. 解剖学报, 2014, 45(4): 561-568.
[9]	林贤丰;邵营宽;王辉;邵培刚;严夏霖;陈杨;金可可;张建色;梅劲 . 离体大鼠胰腺去细胞生物支架的制备与鉴定[J]. , 2012, 43(5): 717-722.
[10]	彭蒙蒙;林贤丰;邵培刚;王辉;张建色;王志斌;梅劲; . 灌注法制备离体大鼠心脏脱细胞基质[J]. , 2012, 43(4): 559-563.
[11]	张建色;王辉;邵培刚;林贤丰;彭蒙蒙;薛向阳;梅劲. 去细胞全肾生物支架的制备与鉴定[J]. , 2012, 43(2): 253-257.
[12]	曲明娟;苑刚;迟晓艳;黄玲.. p38促进尼古丁诱导的大鼠血管平滑肌细胞的细胞外基质表达[J]. , 2012, 43(1): 42-46.
[13]	陈雪;王雪松;李奕;陈颖;高银峰;王晓冬. 整合素-β1在层黏连蛋白促进施万细胞合成细胞外基质过程中的作用[J]. , 2011, 42(4): 465-469.