Research Article

Urinary MicroRNA Analysis Indicates an Epigenetic Regulation of Chronic Kidney Disease of Unknown Etiology in Sri Lanka

Author(s): Thanuri Edirithilake, Nishantha Nanayakkara, Xiao Xiao Lin, Patrick J. Biggs, Rohana Chandrajith, Sampath Lokugalappatti and Saumya Wickramasinghe*

Volume 12, Issue 2, 2023

Published on: 13 March, 2023

Page: [156 - 163] Pages: 8

DOI: 10.2174/2211536612666230202152932

Price: $65

Abstract

Background: Chronic kidney disease of unknown etiology (CKDu) is reported among male paddy farmers in the dry zone of Sri Lanka. The exact cause of this disease remains undetermined. Genetic susceptibility is identified as a major risk factor for CKDu

Objectives: In this study, small urinary RNAs were characterized in CKDu patients, healthy endemic and non-endemic controls. Differently expressed urinary miRNAs and their associated pathways were identified in the study population.

Methods: Healthy and diseased male volunteers (n = 9) were recruited from Girandurukotte (endemic) and Mawanella (non-endemic) districts. Urinary small RNAs were purified and sequenced using Illumina MiSeqTM. The sequence trace files were assembled and analyzed. Differentially ex-pressed miRNAs among these three groups were identified and pathway analysis was conducted.

Results: The urine samples contained 130,623 sequence reads identified as non-coding RNAs, PIWI-interacting RNAs (piRNA), and miRNAs. Approximately four percent of the total small RNA reads represented miRNA, and 29% represented piRNA. A total of 409 miRNA species were ex-pressed in urine. Interestingly, both diseased and endemic controls population showed significantly low expression of miRNA and piRNA. Regardless of the health status, the endemic population ex-pressed significantly low levels of miR-10a, miR-21, miR-148a, and miR-30a which have been linked with several environmental toxins

Conclusion: Significant downregulation of miRNA and piRNA expression in both diseased and healthy endemic samples indicates an epigenetic regulation of CKDu involving genetic and environmental interaction. Further studies of specific miRNA species are required to develop a miRNA panel to identify individuals susceptible to CKDu.

Keywords: miRNA, epigenetics, CKDu, urinary RNA, sequencing, piRNA.

Graphical Abstract
[1]
Bartel DP. MicroRNAs. Cell 2004; 116(2): 281-97.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[2]
Hanna J, Hossain GS, Kocerha J. The potential for microRNA therapeutics and clinical research. Front Genet 2019; 10: 478.
[http://dx.doi.org/10.3389/fgene.2019.00478] [PMID: 31156715]
[3]
Bissels U, Bosio A, Wagner W. MicroRNAs are shaping the hematopoietic landscape. Haematologica 2012; 97(2): 160-7.
[http://dx.doi.org/10.3324/haematol.2011.051730] [PMID: 22058204]
[4]
Shivdasani RA. MicroRNAs: Regulators of gene expression and cell differentiation. Blood 2006; 108(12): 3646-53.
[http://dx.doi.org/10.1182/blood-2006-01-030015] [PMID: 16882713]
[5]
Mishima T, Mizuguchi Y, Kawahigashi Y, Takizawa T, Takizawa T. RT-PCR-based analysis of microRNA (miR-1 and -124) expression in mouse CNS. Brain Res 2007; 1131(1): 37-43.
[http://dx.doi.org/10.1016/j.brainres.2006.11.035] [PMID: 17182009]
[6]
Chang J, Nicolas E, Marks D, et al. MiR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 2004; 1(2): 106-13.
[http://dx.doi.org/10.4161/rna.1.2.1066] [PMID: 17179747]
[7]
Condrat CE, Thompson DC, Barbu MG, et al. MiRNAs as biomarkers in disease: Latest findings regarding their role in diagnosis and prognosis. Cells 2020; 9(2): 276.
[http://dx.doi.org/10.3390/cells9020276] [PMID: 31979244]
[8]
Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010; 56(11): 1733-41.
[http://dx.doi.org/10.1373/clinchem.2010.147405] [PMID: 20847327]
[9]
Benmoussa A, Provost P. Milk microRNAs in health and disease. Compr Rev Food Sci Food Saf 2019; 18(3): 703-22.
[http://dx.doi.org/10.1111/1541-4337.12424] [PMID: 33336926]
[10]
Sohel MH. Extracellular/circulating microRNAs: Release mechanisms, functions and challenges. Achieve Life Sci 2016; 10(2): 175-86.
[http://dx.doi.org/10.1016/j.als.2016.11.007]
[11]
Shapiro O, Bratslavsky G. Genetic diseases. Brenner’s Encyclopidia Genetics. (2nd ed.). Amstaden: Elsevier 2013; pp. 246-7.
[http://dx.doi.org/10.1016/B978-0-12-374984-0.00614-8]
[12]
Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatr Res 2007; 61(5 Part 2): 24R-9R.
[http://dx.doi.org/10.1203/pdr.0b013e3180457684] [PMID: 17413852]
[13]
Piletič K, Kunej T. MicroRNA epigenetic signatures in human disease. Arch Toxicol 2016; 90(10): 2405-19.
[http://dx.doi.org/10.1007/s00204-016-1815-7] [PMID: 27557899]
[14]
Miguel V, Cui JY, Daimiel L, et al. The role of microRNAs in environmental risk factors, noise-induced hearing loss, and mental stress. Antioxid Redox Signal 2018; 28(9): 773-96.
[http://dx.doi.org/10.1089/ars.2017.7175] [PMID: 28562070]
[15]
Vrijens K, Bollati V, Nawrot TS. MicroRNAs as potential signatures of environmental exposure or effect: A systematic review. Environ Health Perspect 2015; 123(5): 399-411.
[http://dx.doi.org/10.1289/ehp.1408459] [PMID: 25616258]
[16]
Russ R, Slack FJ. Cigarette-smoke-induced dysregulation of microRNA expression and its role in lung carcinogenesis. Pulm Med 2012; 2012: 1-9.
[http://dx.doi.org/10.1155/2012/791234] [PMID: 22191027]
[17]
Vliegenthart ADB, Antoine DJ, Dear JW. Target biomarker profile for the clinical management of paracetamol overdose. Br J Clin Pharmacol 2015; 80(3): 351-62.
[http://dx.doi.org/10.1111/bcp.12699] [PMID: 26076366]
[18]
Almaguer M, Herrera R, Orantes CM. Chronic kidney disease of unknown etiology in agricultural communities. MEDICC Rev 2014; 16(2): 9-15.
[http://dx.doi.org/10.37757/MR2014.V16.N2.3] [PMID: 24878644]
[19]
Athuraliya NTC, Abeysekera TDJ, Amerasinghe PH, et al. Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney Int 2011; 80(11): 1212-21.
[http://dx.doi.org/10.1038/ki.2011.258] [PMID: 21832982]
[20]
S Herath HMA, Kawakami T, Nagasawa S. Arsenic, cadmium, lead, and chromium in well water, rice, and human urine in Sri Lanka in relation to chronic kidney disease of unknown etiology. J Water Health 2018; 16(2): 212-22.
[http://dx.doi.org/10.2166/wh.2018.070] [PMID: 29676757]
[21]
Kulathunga MRDL, Ayanka WMA, Naidu R, Wijeratne AW. Chronic kidney disease of unknown aetiology in Sri Lanka and the exposure to environmental chemicals: A review of literature. Environ Geochem Health 2019; 41(5): 2329-38.
[http://dx.doi.org/10.1007/s10653-019-00264-z] [PMID: 30815780]
[22]
Nanayakkara S, Senevirathna STMLD, Harada KH, Chandrajith R, Nanayakkara N, Koizumi A. The Influence of fluoride on chronic kidney disease of uncertain aetiology (CKDu) in Sri Lanka. Chemosphere 2020; 257: 127186.
[http://dx.doi.org/10.1016/j.chemosphere.2020.127186] [PMID: 32516669]
[23]
Perera WPRT, Dayananda MDNR, Liyanage JA. Exploring the root cause for chronic kidney disease of unknown etiology (CKDu) via analysis of metal ion and counterion contaminants in drinking water: a study in Sri Lanka. J Chem 2020; 2020: 1-9.
[http://dx.doi.org/10.1155/2020/8670974]
[24]
Sunil-Chandra NP, Jayaweera JAAS, Kumbukgolla W, Jayasundara MVML. Association of hantavirus infections and leptospirosis with the occurrence of chronic kidney disease of uncertain etiology in the north central province of Sri Lanka: A prospective study with patients and healthy persons. Front Cell Infect Microbiol 2020; 10: 556737.
[http://dx.doi.org/10.3389/fcimb.2020.556737]
[25]
Nanayakkara S, Senevirathna STMLD, Parahitiyawa NB, et al. Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region, Sri Lanka. Environ Health Prev Med 2015; 20(5): 354-9.
[http://dx.doi.org/10.1007/s12199-015-0475-1] [PMID: 26108971]
[26]
Jayasekara JMKB, Dissanayake DM, Adhikari SB, Bandara P. Geographical distribution of chronic kidney disease of unknown origin in North central region of Sri Lanka. Ceylon Med J 2013; 58(1): 6-10.
[http://dx.doi.org/10.4038/cmj.v58i1.5356] [PMID: 23549716]
[27]
Lunyera J, Mohottige D, Isenburg MV, Jeuland M, Patel UD, Stanifer JW. CKD of uncertain etiology: A systematic review. Clin J Am Soc Nephrol 2016; 11(3): 379-85.
[http://dx.doi.org/10.2215/CJN.07500715] [PMID: 26712810]
[28]
Wei Q, Mi QS, Dong Z. The regulation and function of microRNAs in kidney diseases. IUBMB Life 2013; 65(7): 602-14.
[http://dx.doi.org/10.1002/iub.1174] [PMID: 23794512]
[29]
Cox MP, Peterson DA, Biggs PJ. Solexa QA: At-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinformatics 2010; 11(1): 485.
[http://dx.doi.org/10.1186/1471-2105-11-485] [PMID: 20875133]
[30]
Vlachos IS, Kostoulas N, Vergoulis T, et al. DIANA miRPath v.2.0: Investigating the combinatorial effect of microRNAs in pathways. Nucleic Acids Res 2012; 40(W1): W498-504.
[http://dx.doi.org/10.1093/nar/gks494] [PMID: 22649059]
[31]
Neal CS, Michael MZ, Pimlott LK, Yong TY, Li JYZ, Gleadle JM. Circulating microRNA expression is reduced in chronic kidney disease. Nephrol Dial Transplant 2011; 26(11): 3794-802.
[http://dx.doi.org/10.1093/ndt/gfr485] [PMID: 21891774]
[32]
Li M, Huo X, Davuljigari CB, Dai Q, Xu X. MicroRNAs and their role in environmental chemical carcinogenesis. Environ Geochem Health 2019; 41(1): 225-47.
[http://dx.doi.org/10.1007/s10653-018-0179-8] [PMID: 30171477]
[33]
Bird A. Perceptions of epigenetics. Nature 2007; 447(7143): 396-8.
[http://dx.doi.org/10.1038/nature05913] [PMID: 17522671]
[34]
Lacal I, Ventura R. Epigenetic inheritance: Concepts, mechanisms and perspectives. Front Mol Neurosci 2018; 11: 292.
[http://dx.doi.org/10.3389/fnmol.2018.00292] [PMID: 30323739]
[35]
Wei JW, Huang K, Yang C, Kang CS. Non-coding RNAs as regulators in epigenetics. Oncol Rep 2017; 37(1): 3-9.
[http://dx.doi.org/10.3892/or.2016.5236] [PMID: 27841002]
[36]
Yao Q, Chen Y, Zhou X. The roles of microRNAs in epigenetic regulation. Curr Opin Chem Biol 2019; 51: 11-7.
[http://dx.doi.org/10.1016/j.cbpa.2019.01.024] [PMID: 30825741]
[37]
Liu X, Chen X, Yu X, et al. Regulation of microRNAs by epigenetics and their interplay involved in cancer. J Exp Clin Cancer Res 2013; 32(1): 96.
[http://dx.doi.org/10.1186/1756-9966-32-96] [PMID: 24261995]
[38]
Zhang B, Pan X. RDX induces aberrant expression of microRNAs in mouse brain and liver. Environ Health Perspect 2009; 117(2): 231-40.
[http://dx.doi.org/10.1289/ehp.11841] [PMID: 19270793]
[39]
Xu M, Yu Z, Hu F, et al. Identification of differential plasma miRNA profiles in Chinese workers with occupational lead exposure. Biosci Rep 2017; 37(5): BSR20171111.
[http://dx.doi.org/10.1042/BSR20171111] [PMID: 28916729]
[40]
Kong APS, Xiao K, Choi KC, et al. Associations between microRNA (miR-21, 126, 155 and 221), albuminuria and heavy metals in Hong Kong Chinese adolescents. Clin Chim Acta 2012; 413(13-14): 1053-7.
[http://dx.doi.org/10.1016/j.cca.2012.02.014] [PMID: 22405870]
[41]
Kim JH, Cho YH, Hong YC. MicroRNA expression in response to bisphenol A is associated with high blood pressure. Environ Int 2020; 141: 105791.
[http://dx.doi.org/10.1016/j.envint.2020.105791] [PMID: 32438192]
[42]
Wasana HMS, Aluthpatabendi D, Kularatne WMTD, Wijekoon P, Weerasooriya R, Bandara J. Drinking water quality and chronic kidney disease of unknown etiology (CKDu): Synergic effects of fluoride, cadmium and hardness of water. Environ Geochem Health 2016; 38(1): 157-68.
[http://dx.doi.org/10.1007/s10653-015-9699-7] [PMID: 25859936]
[43]
Ananda JTB, Jayaruwan BTWMA, Mahawithanage STC, Wansapala MAJ, Galappaththi SPL. A quantitative analysis of chronic exposure of selected heavy metals in a model diet in a CKD hotspot in Sri Lanka. BMC Nephrol 2019; 20(1): 208.
[http://dx.doi.org/10.1186/s12882-019-1371-5] [PMID: 31174487]
[44]
Paranagama DGA, Bhuiyan MA, Jayasuriya N. Factors associated with chronic kidney disease of unknown aetiology (CKDu) in North central province of Sri Lanka: A comparative analysis of drinking water samples. Appl Water Sci 2018; 8(6): 151.
[http://dx.doi.org/10.1007/s13201-018-0792-9]
[45]
Balasooriya S, Munasinghe H, Herath AT, et al. Possible links between groundwater geochemistry and chronic kidney disease of unknown etiology (CKDu): An investigation from the Ginnoruwa region in Sri Lanka. Expo Health 2020; 12(4): 823-34.
[http://dx.doi.org/10.1007/s12403-019-00340-w]
[46]
Jayatilake N, Mendis S, Maheepala P, Mehta FR. Chronic kidney disease of uncertain aetiology: Prevalence and causative factors in a developing country. BMC Nephrol 2013; 14(1): 180.
[http://dx.doi.org/10.1186/1471-2369-14-180] [PMID: 23981540]
[47]
Czech B, Hannon GJ. One loop to rule them all: The ping-pong cycle and piRNA-guided silencing. Trends Biochem Sci 2016; 41(4): 324-37.
[http://dx.doi.org/10.1016/j.tibs.2015.12.008] [PMID: 26810602]
[48]
Huang XA, Yin H, Sweeney S, Raha D, Snyder M, Lin H. A major epigenetic programming mechanism guided by piRNAs. Dev Cell 2013; 24(5): 502-16.
[http://dx.doi.org/10.1016/j.devcel.2013.01.023] [PMID: 23434410]
[49]
Liu Y, Dou M, Song X, et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer 2019; 18(1): 123.
[http://dx.doi.org/10.1186/s12943-019-1052-9] [PMID: 31399034]
[50]
Eslava-Avilés E, Arenas-Huertero F. piRNAs: Nature, biogenesis, regulation, and their potential clinical utility. Bol Méd Hosp Infant México 2021; 78(5): 432-42.
[http://dx.doi.org/10.24875/BMHIM.20000185] [PMID: 34571517]
[51]
Wu X, Pan Y, Fang Y, et al. The biogenesis and functions of piRNAs in human diseases. Mol Ther Nucleic Acids 2020; 21: 108-20.
[http://dx.doi.org/10.1016/j.omtn.2020.05.023] [PMID: 32516734]
[52]
Yu Y, Xiao J, Hann SS. The emerging roles of PIWI-interacting RNA in human cancers. Cancer Manag Res 2019; 11: 5895-909.
[http://dx.doi.org/10.2147/CMAR.S209300] [PMID: 31303794]
[53]
Kang HM, Ahn SH, Choi P, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 2015; 21(1): 37-46.
[http://dx.doi.org/10.1038/nm.3762] [PMID: 25419705]
[54]
Simon N, Hertig A. Alteration of fatty acid oxidation in tubular epithelial cells: From acute kidney injury to renal fibrogenesis. Front Med (Lausanne) 2015; 2: 52.
[http://dx.doi.org/10.3389/fmed.2015.00052] [PMID: 26301223]
[55]
Wijetunge S, Ratnatunga NVI, Abeysekera TDJ, Wazil AWM, Selvarajah M. Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages. Indian J Nephrol 2015; 25(5): 274-80.
[http://dx.doi.org/10.4103/0971-4065.145095] [PMID: 26628792]
[56]
Chung KW, Lee EK, Lee MK, Oh GT, Yu BP, Chung HY. Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging. J Am Soc Nephrol 2018; 29(4): 1223-37.
[http://dx.doi.org/10.1681/ASN.2017070802] [PMID: 29440279]
[57]
Böttinger EP, Bitzer M. TGF-β signaling in renal disease. J Am Soc Nephrol 2002; 13(10): 2600-10.
[http://dx.doi.org/10.1097/01.ASN.0000033611.79556.AE] [PMID: 12239251]
[58]
Perco P, Pleban C, Kainz A, et al. Protein biomarkers associated with acute renal failure and chronic kidney disease. Eur J Clin Invest 2006; 36(11): 753-63.
[http://dx.doi.org/10.1111/j.1365-2362.2006.01729.x] [PMID: 17032342]

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