药学学报, 2019, 54(11): 1918-1925
王伟达, 李昭君, 陈园园, 陈晓光, 张森. LncRNA与慢性肾脏病的研究进展[J]. 药学学报, 2019, 54(11): 1918-1925.
WANG Wei-da, LI Zhao-jun, CHEN Yuan-yuan, CHEN Xiao-guang, ZHANG Sen. Recent advances in LncRNAs and chronic kidney disease[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 1918-1925.

王伟达, 李昭君, 陈园园, 陈晓光, 张森
中国医学科学院、北京协和医学院药物研究所, 北京 100050
长链非编码RNA(long noncoding RNA,LncRNA)是一类不具备或较少具备编码能力的转录本。近年来,这些曾被认为是基因转录组“噪音”的LncRNA受到了极大的关注,并正成为生物调节中潜在的重要参与者。LncRNA具有广泛的生物学功能,其异常表达与癌症、免疫疾病和代谢疾病等多种疾病相关。慢性肾脏病(chronic kidney disease,CKD)在全球不同地区的发病率为10%~15%,具有增长率高、不知晓率高的特点。主要有糖尿病肾病、膜性肾病以及各种免疫介导的肾小球疾病。现在已有不少研究证据表明,LncRNA与肾脏有着密切的联系,或许可成为新的治疗靶点或新的生物标志物来诊断疾病的发生发展。本文将对LncRNA的功能以及LncRNA与各种慢性肾脏疾病的现有研究做一总结,并展望了LncRNA在治疗CKD方面临床应用的前景。
关键词:    长链非编码RNA      糖尿病肾病      膜性肾病      狼疮性肾炎      IgA肾炎      慢性肾脏病     
Recent advances in LncRNAs and chronic kidney disease
WANG Wei-da, LI Zhao-jun, CHEN Yuan-yuan, CHEN Xiao-guang, ZHANG Sen
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Long non-coding RNAs (LncRNAs), defined as transcripts which are hundreds of nucleotides with little or non-protein coding potential. Recently, LncRNAs have caught much more attentions, instead of considering as noises of genome transcripts, and indeed they have been found to play important roles associated with some biological processes, such as tumorigenesis, immunology dysfunction, metabolism adjustment, and so on. The incidence of chronic kidney disease (CKD) in different regions of the world is about 10% to 15%, with high growth rate and high unawareness, including the diabetic nephropathy, membranous nephropathy, etc. Previous publications also suggest that LncRNAs have a close relationship with the kidneys, and it may become new therapeutic targets or new biomarkers to diagnose diseases. In this review, we will summarize LncRNAs' functions with chronic kidney diseases, and discuss the prospects of the clinical applications of LncRNAs in the treatment of CKD treatment.
Key words:    long non-coding RNA    diabetic nephropathy    membranous nephropathy    lupus nephritis    IgA glomerulonephritis    chronic kidney disease   
收稿日期: 2019-06-12
DOI: 10.16438/j.0513-4870.2019-0464
基金项目: 十三五“重大新药创制”科技重大专项(2018ZX09711001).
PDF(441KB) Free
王伟达  在本刊中的所有文章
李昭君  在本刊中的所有文章
陈园园  在本刊中的所有文章
陈晓光  在本刊中的所有文章
张森  在本刊中的所有文章

[1] Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future[J]. Genetics, 2013, 193: 651-669.
[2] Cheng J, Kapranov P, Drenkow J, et al. Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution[J]. Science, 2005, 308: 1149-1154.
[3] Brosnan CA, Voinnet O. The long and the short of noncoding RNAs[J]. Curr Opin Cell Biol, 2009, 21: 416-425.
[4] Kour S, Rath PC. Long noncoding RNAs in aging and age-related diseases[J]. Ageing Res Rev, 2016, 26: 1-21.
[5] Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function[J]. Nat Rev Genet, 2016, 17: 47-62.
[6] Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs[J]. Cell, 2009, 136: 629-641.
[7] Gao JP, Zhang SJ, Luo ZH, et al. Impact of long non-coding RNA CCAT1 on the tumor sensitivity to radiotherapy in nude mice transplanted with human cervical cancer cells XB1702[J]. Chin Med Biotechnol (中国医药生物技术), 2017, 12: 40-44.
[8] Niu CY, Xue LL, Ji H, et al. Progress in research on biological function of lncRNA[J]. Chin J Biol (中国生物制品学杂志), 2019, 32: 228-232, 237.
[9] Postepska-Igielska A, Giwojna A, Gasri-Plotnitsky L, et al. LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure[J]. Mol Cell, 2015, 60: 626-636.
[10] Lin N, Chang KY, Li Z, et al. An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment[J]. Mol Cell, 2014, 53: 1067.
[11] Wang P, Xue Y, Han Y, et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation[J]. Science, 2014, 344: 310-313.
[12] Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs[J]. Mol Cell, 2011, 43: 904-914.
[13] Pandey RR, Mondal T, Mohammad F, et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation[J]. Mol Cell, 2008, 32: 232-246.
[14] Tripathi V, Ellis JD, Shen Z, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation[J]. Mol Cell, 2010, 39: 925-938.
[15] Han P, Li W, Lin CH, et al. A long noncoding RNA protects the heart from pathological hypertrophy[J]. Nature, 2014, 514: 102-106.
[16] Grote P, Wittler L, Hendrix D, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse[J]. Dev Cell, 2013, 24: 206-214.
[17] Aguilo F, Zhou MM, Walsh MJ. Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression[J]. Cancer Res, 2011, 71: 5365-5369.
[18] Lan JQ, Zhu CJ. Recent advances in pharmacological intervention for prediabetes[J]. Acta Pharm Sin (药学学报), 2015, 50: 1565-1572.
[19] Paraskevopoulou MD, Hatzigeorgiou AG. Analyzing mirna-lncRNA interactions[J]. Methods Mol Biol, 2016, 1402: 271-286.
[20] Duan LJ, Ding M, Hou LJ, et al. Long noncoding RNA TUG1 alleviates extracellular matrix accumulation via mediating microRNA-377 targeting of PPARgamma in diabetic nephropathy[J]. Biochem Biophys Res Commun, 2017, 484: 598-604.
[21] Wang X, Xu Y, Zhu YC, et al. LncRNA NEAT1 promotes extracellular matrix accumulation and epithelial-to-mesenchymal transition by targeting miR-27b-3p and ZEB1 in diabetic nephropathy[J]. J Cell Physiol, 2019, 234: 12926-12933.
[22] Li X, Zeng L, Cao C, et al. Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy[J]. Exp Cell Res, 2017, 350: 327-335.
[23] Alvarez ML, Khosroheidari M, Eddy E, et al. Role of microRNA 1207-5P and its host gene, the long non-coding RNA Pvt1, as mediators of extracellular matrix accumulation in the kidney: implications for diabetic nephropathy[J]. PLoS One, 2013, 8: e77468.
[24] Kato M, Wang M, Chen Z, et al. An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy[J]. Nat Commun, 2016, 7: 12864.
[25] Hu M, Wang R, Li X, et al. LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose-induced podocyte injury via its interplay with beta-catenin[J]. J Cell Mol Med, 2017, 21: 2732-2747.
[26] Li Y, Ren D, Xu G. Long noncoding RNA MALAT1 mediates high glucose-induced glomerular endothelial cell injury by epigenetically inhibiting klotho via methyltransferase G9a[J]. IUBMB Life, 2019, 71: 873-881.
[27] Long J, Badal SS, Ye Z, et al. Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy[J]. J Clin Invest, 2016, 126: 4205-4218.
[28] Millis MP, Bowen D, Kingsley C, et al. Variants in the plasmacytoma variant translocation gene (PVT1) are associated with end-stage renal disease attributed to type 1 diabetes[J]. Diabetes, 2007, 56: 3027-3032.
[29] Hanson RL, Craig DW, Millis MP, et al. Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study[J]. Diabetes, 2007, 56: 975.
[30] Alvarez ML, DiStefano JK. Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy[J]. PLoS One, 2011, 6: e18671.
[31] Zhang R, Li J, Huang T, et al. Danggui buxue tang suppresses high glucose-induced proliferation and extracellular matrix accumulation of mesangial cells via inhibiting lncRNA PVT1[J]. Am J Transl Res, 2017, 9: 3732-3740.
[32] Huang S, Xu Y, Ge X, et al. Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway[J]. J Cell Physiol, 2019, 234: 11200-11207.
[33] Wang M, Wang S, Yao D, et al. A novel long non-coding RNA CYP4B1-PS1-001 regulates proliferation and fibrosis in diabetic nephropathy[J]. Mol Cell Endocrinol, 2016, 426: 136-145.
[34] Wang S, Chen X, Wang M, et al. Long non-coding RNA CYP4B1-PS1-001 inhibits proliferation and fibrosis in diabetic nephropathy by interacting with nucleolin[J]. Cell Physiol Biochem, 2018, 49: 2174-2187.
[35] Bai X, Geng J, Li X, et al. Long Noncoding RNA LINC01619 regulates microRNA-27a/forkhead box protein O1 and endoplasmic reticulum stress-mediated podocyte injury in diabetic nephropathy[J]. Antioxid Redox Signal, 2018, 29: 355-376.
[36] Ji TT, Wang YK, Zhu YC, et al. Long noncoding RNA Gm6135 functions as a competitive endogenous RNA to regulate toll-like receptor 4 expression by sponging miR-203-3p in diabetic nephropathy[J]. J Cell Physiol, 2019, 234: 6633-6641.
[37] Li A, Peng R, Sun Y, et al. LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via miR-34a-5p/Sirt1/HIF-1alpha signaling[J]. Cell Death Dis, 2018, 9: 461.
[38] Zhang Y, Sun Y, Peng R, et al. The long noncoding RNA 150Rik promotes mesangial cell proliferation via miR-451/IGF1R/p38 MAPK signaling in diabetic nephropathy[J]. Cell Physiol Biochem, 2018, 51: 1410-1428.
[39] Fan W, Peng Y, Liang Z, et al. A negative feedback loop of H19/miR-675/EGR1 is involved in diabetic nephropathy by downregulating the expression of the vitamin D receptor[J]. J Cell Physiol, 2019, 234: 17505-17513.
[40] Chen HY, Zhong X, Huang XR, et al. microRNA-29b inhibits diabetic nephropathy in db/db mice[J]. Mol Ther, 2014, 22: 842-853.
[41] Sun SF, Tang PMK, Feng M, et al. Novel lncRNA Erbb4-IR promotes diabetic kidney injury in db/db mice by targeting miR-29b[J]. Diabetes, 2018, 67: 731-744.
[42] Wang J, Pan J, Li H, et al. lncRNA ZEB1-AS1 was suppressed by p53 for renal fibrosis in diabetic nephropathy[J]. Mol Ther Nucleic Acids, 2018, 12: 741-750.
[43] Shang J, Wang S, Jiang Y, et al. Identification of key lncRNAs contributing to diabetic nephropathy by gene co-expression network analysis[J]. Sci Rep, 2019, 9: 3328.
[44] Wang YZ, Zhu DY, Xie XM, et al. EA15, MIR22, LINC00472 as diagnostic markers for diabetic kidney disease[J]. J Cell Physiol, 2019, 234: 8797-8803.
[45] Tang W, Zhang D, Ma X. RNA-sequencing reveals genome-wide long non-coding RNAs profiling associated with early development of diabetic nephropathy[J]. Oncotarget, 2017, 8: 105832-105847.
[46] Han R, Hu S, Qin W, et al. Upregulated long noncoding RNA LOC105375913 induces tubulointerstitial fibrosis in focal segmental glomerulosclerosis[J]. Sci Rep, 2019, 9: 716.
[47] Hu S, Han R, Shi J, et al. The long noncoding RNA LOC105374325 causes podocyte injury in individuals with focal segmental glomerulosclerosis[J]. J Biol Chem, 2018, 293: 20227-20239.
[48] Huang YS, Hsieh HY, Shih HM, et al. Urinary Xist is a potential biomarker for membranous nephropathy[J]. Biochem Biophys Res Commun, 2014, 452: 415-421.
[49] Jin LW, Pan M, Ye HY, et al. Down-regulation of the long non-coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR-217-TLR4 pathway[J]. Exp Physiol, 2019, 104: 220-230.
[50] Liao Z, Ye Z, Xue Z, et al. Identification of Renal Long Non-coding RNA RP11-2B6.2 as a positive regulator of type i interferon signaling pathway in lupus nephritis[J]. Front Immunol, 2019, 10: 975.
[51] Wu Y, Zhang F, Ma J, et al. Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus[J]. Arthritis Res Ther, 2015, 17: 131.
[52] Zuo N, Li Y, Liu N, et al. Differentially expressed long noncoding RNAs and mRNAs in patients with IgA nephropathy[J]. Mol Med Rep, 2017, 16: 7724-7730.