Identification of differentially expressed miRNAs associated with chronic kidney disease–mineral bone disorder
Kyung Im Kim1, Sohyun Jeong2, Nayoung Han2, Jung Mi Oh2, Kook-Hwan Oh3, In-Wha Kim2()
1. College of Pharmacy, Korea University, Sejong 30019, Republic of Korea 2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea 3. Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea
The purpose of this study is to characterize a meta-signature of differentially expressed mRNA in chronic kidney disease (CKD) to predict putative microRNA (miRNA) in CKD–mineral bone disorder (CKD–MBD) and confirm the changes in these genes and miRNA expression under uremic conditions by using a cell culture system. PubMed searches using MeSH terms and keywords related to CKD, uremia, and mRNA arrays were conducted. Through a computational analysis, a meta-signature that characterizes the significant intersection of differentially expressed mRNA and expected miRNAs associated with CKD–MBD was determined. Additionally, changes in gene and miRNA expressions under uremic conditions were confirmed with human Saos-2 osteoblast-like cells. A statistically significant mRNA meta-signature of upregulated and downregulated mRNA levels was identified. Furthermore, miRNA expression profiles were inferred, and computational analyses were performed with the imputed microRNA regulation based on weighted ranked expression and putative microRNA targets (IMRE) method to identify miRNAs associated with CKD occurrence. TLR4 and miR-146b levels were significantly associated with CKD–MBD. TLR4 levels were significantly downregulated, whereas pri-miR-146b and miR-146b were upregulated in the presence of uremic toxins in human Saos-2 osteoblast-like cells. Differentially expressed miRNAs associated with CKD-MBD were identified through a computational analysis, and changes in gene and miRNA expressions were confirmed with an in vitro cell culture system.
Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A; European Uremic Toxin Work Group. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 2012; 23(7): 1258–1270 https://doi.org/10.1681/ASN.2011121175
pmid: 22626821
3
Cibulka R, Racek J. Metabolic disorders in patients with chronic kidney failure. Physiol Res 2007; 56(6): 697–705
pmid: 17298212
4
Lanza D, Perna AF, Oliva A, Vanholder R, Pletinck A, Guastafierro S, Di Nunzio A, Vigorito C, Capasso G, Jankowski V, Jankowski J, Ingrosso D. Impact of the uremic milieu on the osteogenic potential of mesenchymal stem cells. PLoS One 2015; 10(1): e0116468 https://doi.org/10.1371/journal.pone.0116468
pmid: 25635832
5
Meijers BK, Claes K, Bammens B, de Loor H, Viaene L, Verbeke K, Kuypers D, Vanrenterghem Y, Evenepoel P. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 2010; 5(7): 1182–1189 https://doi.org/10.2215/CJN.07971109
pmid: 20430946
6
Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G; Kidney Disease: Improving Global Outcomes (KDIGO). Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69(11): 1945–1953 https://doi.org/10.1038/sj.ki.5000414
pmid: 16641930
Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development 2005; 132(21): 4653–4662 https://doi.org/10.1242/dev.02073
pmid: 16224045
11
O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010; 10(2): 111–122 https://doi.org/10.1038/nri2708
pmid: 20098459
12
Tili E, Michaille JJ, Croce CM. MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol Rev 2013; 253(1): 167–184 https://doi.org/10.1111/imr.12050
pmid: 23550646
Schöler N, Langer C, Döhner H, Buske C, Kuchenbauer F. Serum microRNAs as a novel class of biomarkers: a comprehensive review of the literature. Exp Hematol 2010; 38(12): 1126–1130 https://doi.org/10.1016/j.exphem.2010.10.004
pmid: 20977925
15
Isakova T, Gutiérrez OM, Patel NM, Andress DL, Wolf M, Levin A. Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions. J Ren Nutr 2011; 21(4): 295–302 https://doi.org/10.1053/j.jrn.2010.07.002
pmid: 20817560
16
Fang Y, Ginsberg C, Seifert M, Agapova O, Sugatani T, Register TC, Freedman BI, Monier-Faugere MC, Malluche H, Hruska KA. CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol 2014; 25(8): 1760–1773 https://doi.org/10.1681/ASN.2013080818
pmid: 24578135
17
Neal CS, Michael MZ, Pimlott LK, Yong TY, Li JY, Gleadle JM. Circulating microRNA expression is reduced in chronic kidney disease. Nephrol Dial Transplant 2011; 26(11): 3794–3802 https://doi.org/10.1093/ndt/gfr485
pmid: 21891774
18
Beltrami C, Clayton A, Phillips AO, Fraser DJ, Bowen T. Analysis of urinary microRNAs in chronic kidney disease. Biochem Soc Trans 2012; 40(4): 875–879 https://doi.org/10.1042/BST20120090
pmid: 22817751
19
Feichtinger J, McFarlane RJ, Larcombe LD. CancerMA: a web-based tool for automatic meta-analysis of public cancer microarray data. Database (Oxford) 2012; 2012: bas055
20
Ramasamy A, Mondry A, Holmes CC, Altman DG. Key issues in conducting a meta-analysis of gene expression microarray datasets. PLoS Med 2008; 5(9): e184 https://doi.org/10.1371/journal.pmed.0050184
pmid: 18767902
21
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5(10): R80 https://doi.org/10.1186/gb-2004-5-10-r80
pmid: 15461798
Lee Y, Yang X, Huang Y, Fan H, Zhang Q, Wu Y, Li J, Hasina R, Cheng C, Lingen MW, Gerstein MB, Weichselbaum RR, Xing HR, Lussier YA. Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis. PLOS Comput Biol 2010; 6(4): e1000730 https://doi.org/10.1371/journal.pcbi.1000730
pmid: 20369013
Bauer O, Sharir A, Kimura A, Hantisteanu S, Takeda S, Groner Y. Loss of osteoblast Runx3 produces severe congenital osteopenia. Mol Cell Biol 2015; 35(7): 1097–1109 https://doi.org/10.1128/MCB.01106-14
pmid: 25605327
26
Kim HJ, Park J, Lee SK, Kim KR, Park KK, Chung WY. Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer. J Pathol 2015; 237(4): 520–531 https://doi.org/10.1002/path.4597
pmid: 26239696
27
Reppe S, Refvem H, Gautvik VT, Olstad OK, Høvring PI, Reinholt FP, Holden M, Frigessi A, Jemtland R, Gautvik KM. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone 2010; 46(3): 604–612 https://doi.org/10.1016/j.bone.2009.11.007
pmid: 19922823
28
Niu G, Li B, Sun J, Sun L. miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met. Cell Prolif 2015; 48(3): 348–355 https://doi.org/10.1111/cpr.12187
pmid: 25880599
29
Huang RL, Yuan Y, Zou GM, Liu G, Tu J, Li Q. LPS-stimulated inflammatory environment inhibits BMP-2-induced osteoblastic differentiation through crosstalk between TLR4/MyD88/NF- kB and BMP/Smad signaling. Stem Cells Dev 2014; 23(3): 277–289 https://doi.org/10.1089/scd.2013.0345
pmid: 24050190
30
Ando M, Shibuya A, Tsuchiya K, Akiba T, Nitta K. Reduced capacity of mononuclear cells to synthesize cytokines against an inflammatory stimulus in uremic patients. Nephron Clin Pract 2006; 104(3): c113–c119 https://doi.org/10.1159/000094446
pmid: 16837784
31
Wang ZS, Xu DM, Guan GJ, Cui MY, Wei Y, Tang LJ, Jia XY, Li WB. Clinical significance of toll-like receptor 4 expression on the surface of peripheral blood mononuclear cells in uremic patients. Natl Med J China (Zhonghua Yi Xue Za Zhi) 2010; 90(34): 2389–2391 (in Chinese)
pmid: 21092506
32
He X, Wang H, Jin T, Xu Y, Mei L, Yang J. TLR4 activation promotes bone marrow MSC proliferation and osteogenic differentiation via Wnt3a and Wnt5a signaling. PLoS One 2016; 11(3): e0149876 https://doi.org/10.1371/journal.pone.0149876
pmid: 26930594
33
Herzmann N, Salamon A, Fiedler T, Peters K. Lipopolysaccharide induces proliferation and osteogenic differentiation of adipose-derived mesenchymal stromal cells in vitro via TLR4 activation. Exp Cell Res 2017; 350(1): 115–122 https://doi.org/10.1016/j.yexcr.2016.11.012
pmid: 27865937
34
Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103(33): 12481–12486 https://doi.org/10.1073/pnas.0605298103
pmid: 16885212
35
Sato T, Liu X, Nelson A, Nakanishi M, Kanaji N, Wang X, Kim M, Li Y, Sun J, Michalski J, Patil A, Basma H, Holz O, Magnussen H, Rennard SI. Reduced miR-146a increases prostaglandin E2 in chronic obstructive pulmonary disease fibroblasts. Am J Respir Crit Care Med 2010; 182(8): 1020–1029 https://doi.org/10.1164/rccm.201001-0055OC
pmid: 20522791
36
Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI, Fish JE. MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med 2013; 5(7): 1017–1034 https://doi.org/10.1002/emmm.201202318
pmid: 23733368
37
Larner-Svensson HM, Williams AE, Tsitsiou E, Perry MM, Jiang X, Chung KF, Lindsay MA. Pharmacological studies of the mechanism and function of interleukin-1β-induced miRNA-146a expression in primary human airway smooth muscle. Respir Res 2010; 11(1): 68 https://doi.org/10.1186/1465-9921-11-68
pmid: 20525168
38
Perry MM, Moschos SA, Williams AE, Shepherd NJ, Larner-Svensson HM, Lindsay MA. Rapid changes in microRNA-146a expression negatively regulate the IL-1β-induced inflammatory response in human lung alveolar epithelial cells. J Immunol 2008; 180(8): 5689–5698 https://doi.org/10.4049/jimmunol.180.8.5689
pmid: 18390754
39
Curtale G, Mirolo M, Renzi TA, Rossato M, Bazzoni F, Locati M. Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc Natl Acad Sci USA 2013; 110(28): 11499–11504 https://doi.org/10.1073/pnas.1219852110
pmid: 23798430
40
Asai Y, Hirokawa Y, Niwa K, Ogawa T. Osteoclast differentiation by human osteoblastic cell line SaOS-2 primed with bacterial lipid A. FEMS Immunol Med Microbiol 2003; 38(1): 71–79 https://doi.org/10.1016/S0928-8244(03)00111-1
pmid: 12900058
41
Fetahu IS, Tennakoon S, Lines KE, Gröschel C, Aggarwal A, Mesteri I, Baumgartner-Parzer S, Mader RM, Thakker RV, Kállay E. miR-135b- and miR-146b-dependent silencing of calcium-sensing receptor expression in colorectal tumors. Int J Cancer 2016; 138(1): 137–145 https://doi.org/10.1002/ijc.29681
pmid: 26178670
42
Bover J, Aguilar A, Baas J, Reyes J, Lloret MJ, Farré N, Olaya M, Canal C, Marco H, Andrés E, Trinidad P, Ballarin J. Calcimimetics in the chronic kidney disease-mineral and bone disorder. Int J Artif Organs 2009; 32(2): 108–121
pmid: 19363783
43
Oishi T, Uezumi A, Kanaji A, Yamamoto N, Yamaguchi A, Yamada H, Tsuchida K. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One 2013; 8(2): e56641 https://doi.org/10.1371/journal.pone.0056641
pmid: 23457598
44
Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, Tranaeus A, Stenvinkel P, Lindholm B. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008; 3(5): 1526–1533 https://doi.org/10.2215/CJN.00950208
pmid: 18701615