Research Article

TRAIL and EGFR Pathways Targeting microRNAs are Predominantly Regulated in Human Diabetic Nephropathy

Author(s): Bhuvnesh Rai, Akshara Pande and Swasti Tiwari*

Volume 12, Issue 2, 2023

Published on: 12 May, 2023

Page: [143 - 155] Pages: 13

DOI: 10.2174/2211536612666230407093841

Price: $65

Abstract

Background: Unbiased microRNA profiling of renal tissue and urinary extracellular vesicles (uEVs) from diabetic nephropathy (DN) subjects may unravel novel targets with diagnostic and therapeutic potential. Here we used the miRNA profile of uEVs and renal biopsies from DN subjects available on the GEO database.

Methods: The miR expression profiles of kidney tissue (GSE51674) and urinary exosomes (GSE48318) from DN and control subjects were obtained by GEO2R tools from Gene Expression Omnibus (GEO) databases. Differentially expressed miRNAs in DN samples, relative to controls, were identified using a bioinformatic pipeline. Targets of miRs commonly regulated in both sample types were predicted by miRWalk, followed by functional gene enrichment analysis. Gene targets were identified by MiRTarBase, TargetScan and MiRDB.

Results: Eight miRs, including let-7c, miR-10a, miR-10b and miR-181c, were significantly regulated in kidney tissue and uEVs in DN subjects versus controls. The top 10 significant pathways targeted by these miRs included TRAIL, EGFR, Proteoglycan syndecan, VEGF and Integrin Pathway. Gene target analysis by miRwalk upon validation using ShinyGO 70 targets with significant miRNA-mRNA interaction.

Conclusion: In silico analysis showed that miRs targeting TRAIL and EGFR signaling are predominately regulated in uEVs and renal tissue of DN subjects. After wet-lab validation, the identified miRstarget pairs may be explored for their diagnostic and/or therapeutic potential in diabetic nephropathy.

Keywords: Renal transcriptome, renal biopsy, urinary exosomes, urinary extracellular vesicles, diabetic nephropathy, vesicles, GEO, ESRD.

Graphical Abstract
[1]
Khan NU, Lin J, Liu X, et al. Insights into predicting diabetic nephropathy using urinary biomarkers. Biochim Biophys Acta Proteins Proteomics 2020; 1868(10): 140475.
[http://dx.doi.org/10.1016/j.bbapap.2020.140475] [PMID: 32574766]
[2]
Lu Y, Liu D, Feng Q, Liu Z. Diabetic nephropathy: Perspective on extracellular vesicles. Front Immunol 2020; 11: 943.
[http://dx.doi.org/10.3389/fimmu.2020.00943] [PMID: 32582146]
[3]
Sinha N, Kumar V, Puri V, et al. Urinary exosomes: Potential biomarkers for diabetic nephropathy. Nephrology 2020; 25(12): 881-7.
[http://dx.doi.org/10.1111/nep.13720] [PMID: 32323449]
[4]
Yang Y, Xiao L, Li J, Kanwar YS, Liu F, Sun L. Urine miRNAs: Potential biomarkers for monitoring progression of early stages of diabetic nephropathy. Med Hypotheses 2013; 81(2): 274-8.
[http://dx.doi.org/10.1016/j.mehy.2013.04.031] [PMID: 23683774]
[5]
Hortin GL, Sviridov D. Diagnostic potential for urinary proteomics. Pharmacogenomics 2007; 8(3): 237-55.
[http://dx.doi.org/10.2217/14622416.8.3.237] [PMID: 17324112]
[6]
Hoorn EJ, Pisitkun T, Zietse R, et al. Prospects for urinary proteomics: Exosomes as a source of urinary biomarkers (Review Article). Nephrology 2005; 10(3): 283-90.
[http://dx.doi.org/10.1111/j.1440-1797.2005.00387.x] [PMID: 15958043]
[7]
Street JM, Koritzinsky EH, Glispie DM, Star RA, Yuen PST. Urine exosomes. Adv Clin Chem 2017; 78: 103-22.
[http://dx.doi.org/10.1016/bs.acc.2016.07.003] [PMID: 28057185]
[8]
Bang C, Thum T. Exosomes: New players in cell–cell communication. Int J Biochem Cell Biol 2012; 44(11): 2060-4.
[http://dx.doi.org/10.1016/j.biocel.2012.08.007] [PMID: 22903023]
[9]
Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta, Gen Subj 2012; 1820(7): 940-8.
[http://dx.doi.org/10.1016/j.bbagen.2012.03.017] [PMID: 22503788]
[10]
Gu Y, Li M, Wang T, et al. Lactation-related microRNA expression profiles of porcine breast milk exosomes. PLoS One 2012; 7(8): e43691.
[http://dx.doi.org/10.1371/journal.pone.0043691] [PMID: 22937080]
[11]
Keller S, Ridinger J, Rupp AK, Janssen JWG, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med 2011; 9(1): 86.
[http://dx.doi.org/10.1186/1479-5876-9-86] [PMID: 21651777]
[12]
Gonzales P, Pisitkun T, Knepper MA. Urinary exosomes: Is there a future? Nephrol Dial Transplant 2008; 23(6): 1799-801.
[http://dx.doi.org/10.1093/ndt/gfn058] [PMID: 18310721]
[13]
Gonzales PA, Pisitkun T, Hoffert JD, et al. Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol 2009; 20(2): 363-79.
[http://dx.doi.org/10.1681/ASN.2008040406] [PMID: 19056867]
[14]
Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci 2004; 101(36): 13368-73.
[http://dx.doi.org/10.1073/pnas.0403453101] [PMID: 15326289]
[15]
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9.
[http://dx.doi.org/10.1038/ncb1596] [PMID: 17486113]
[16]
Fan Y, Chen H, Huang Z, Zheng H, Zhou J. Emerging role of miRNAs in renal fibrosis. RNA Biol 2020; 17(1): 1-12.
[http://dx.doi.org/10.1080/15476286.2019.1667215] [PMID: 31550975]
[17]
Ha TY. MicroRNAs in human diseases: From cancer to cardiovascular disease. Immune Netw 2011; 11(3): 135-54.
[http://dx.doi.org/10.4110/in.2011.11.3.135] [PMID: 21860607]
[18]
Sayed D, Abdellatif M. MicroRNAs in development and disease. Physiol Rev 2011; 91(3): 827-87.
[http://dx.doi.org/10.1152/physrev.00006.2010] [PMID: 21742789]
[19]
Shi KQ, Lin Z, Chen XJ, et al. Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance. Oncotarget 2015; 6(28): 25093-108.
[http://dx.doi.org/10.18632/oncotarget.4437] [PMID: 26231037]
[20]
Ma Z, Wei Q, Zhang M, Chen JK, Dong Z. Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3. Am J Physiol Renal Physiol 2018; 315(6): F1822-32.
[http://dx.doi.org/10.1152/ajprenal.00402.2018] [PMID: 30280598]
[21]
Wilczynska A, Bushell M. The complexity of miRNA-mediated repression. Cell Death Differ 2015; 22(1): 22-33.
[http://dx.doi.org/10.1038/cdd.2014.112] [PMID: 25190144]
[22]
Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res 2013; 41(Database issue): D991-5.
[PMID: 23193258]
[23]
Benjamini Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc B 1995; 57(1): 289-300.
[http://dx.doi.org/10.1111/j.2517-6161.1995.tb02031.x]
[24]
Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43(7): e47.
[http://dx.doi.org/10.1093/nar/gkv007] [PMID: 25605792]
[25]
McInnes L, Healy J. UMAP: Uniform manifold approximation and projection for dimension reduction. ArXiv e-prints 2018; 03426.
[http://dx.doi.org/10.48550/arXiv.1802.03426]
[26]
McGill R, Tukey JW, Larsen WA. Variations of box plots. Am Stat 1978; 32(1): 12-6.
[27]
Oliveros JC. An interactive tool for comparing lists with venn’s diagrams. Open J Genet 2020; 10(4)
[28]
Chen Y, Wang X. miRDB: An online database for prediction of functional microRNA targets. Nucleic Acids Res 2020; 48(D1): D127-31.
[http://dx.doi.org/10.1093/nar/gkz757] [PMID: 31504780]
[29]
McGeary SE, Lin KS, Shi CY, et al. The biochemical basis of microRNA targeting efficacy. Science 2019; 366(6472): eaav1741.
[http://dx.doi.org/10.1126/science.aav1741] [PMID: 31806698]
[30]
Huang HY, Lin YCD, Cui S, et al. miRTarBase update 2022: An informative resource for experimentally validated miRNA–target interactions. Nucleic Acids Res 2022; 50(D1): D222-30.
[http://dx.doi.org/10.1093/nar/gkab1079] [PMID: 34850920]
[31]
Sticht C, De La Torre C, Parveen A, Gretz N. miRWalk: An online resource for prediction of microRNA binding sites. PLoS One 2018; 13(10): e0206239.
[http://dx.doi.org/10.1371/journal.pone.0206239] [PMID: 30335862]
[32]
Pathan M, Keerthikumar S, Ang CS, et al. FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics 2015; 15(15): 2597-601.
[http://dx.doi.org/10.1002/pmic.201400515] [PMID: 25921073]
[33]
Thomas PD, Ebert D, Muruganujan A, Mushayahama T, Albou LP, Mi H. PANTHER: Making genome‐scale phylogenetics accessible to all. Protein Sci 2022; 31(1): 8-22.
[http://dx.doi.org/10.1002/pro.4218] [PMID: 34717010]
[34]
Ge SX, Jung D, Yao R. Shiny G.O: A graphical gene-set enrichment tool for animals and plants. Bioinformatics 2020; 36(8): 2628-9.
[http://dx.doi.org/10.1093/bioinformatics/btz931] [PMID: 31882993]
[35]
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]
[36]
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]
[37]
Thongboonkerd V. Roles for exosome in various kidney diseases and disorders. Front Pharmacol 2020; 10: 1655.
[http://dx.doi.org/10.3389/fphar.2019.01655] [PMID: 32082158]
[38]
Wu X, Gao Y, Cui F, Zhang N. Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis. Biol Open 2016; 5(4): 484-91.
[http://dx.doi.org/10.1242/bio.015990] [PMID: 27010029]
[39]
Andersen H, Friis UG, Hansen PBL, Svenningsen P, Henriksen JE, Jensen BL. Diabetic nephropathy is associated with increased urine excretion of proteases plasmin, prostasin and urokinase and activation of amiloride-sensitive current in collecting duct cells. Nephrol Dial Transplant 2015; 30(5): 781-9.
[http://dx.doi.org/10.1093/ndt/gfu402] [PMID: 25609736]
[40]
Cartland SP, Erlich JH, Kavurma MM. TRAIL deficiency contributes to diabetic nephropathy in fat-fed ApoE-/- mice. PLoS One 2014; 9(3): e92952.
[http://dx.doi.org/10.1371/journal.pone.0092952] [PMID: 24667560]
[41]
Lorz C, Benito-Martín A, Boucherot A, et al. The death ligand TRAIL in diabetic nephropathy. J Am Soc Nephrol 2008; 19(5): 904-14.
[http://dx.doi.org/10.1681/ASN.2007050581] [PMID: 18287563]
[42]
Chen J, Chen JK, Nagai K, et al. EGFR signaling promotes TGFβ-dependent renal fibrosis. J Am Soc Nephrol 2012; 23(2): 215-24.
[http://dx.doi.org/10.1681/ASN.2011070645] [PMID: 22095949]
[43]
Chen J, Chen JK, Harris RC. EGF receptor deletion in podocytes attenuates diabetic nephropathy. J Am Soc Nephrol 2015; 26(5): 1115-25.
[http://dx.doi.org/10.1681/ASN.2014020192] [PMID: 25185988]
[44]
Götte M, Echtermeyer F. Syndecan-1 as a regulator of chemokine function. ScientificWorldJournal 2003; 3: 1327-31.
[http://dx.doi.org/10.1100/tsw.2003.118] [PMID: 14755113]
[45]
Svennevig K, Kolset SO, Bangstad HJ. Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients. Diabetologia 2006; 49(9): 2214-6.
[http://dx.doi.org/10.1007/s00125-006-0330-4] [PMID: 16832664]
[46]
Tufro A, Veron D. VEGF and podocytes in diabetic nephropathy. Semin Nephrol 2012; 32(4): 385-93.
[http://dx.doi.org/10.1016/j.semnephrol.2012.06.010] [PMID: 22958493]
[47]
Ishii H, Aoyama T, Takahashi H, et al. Treatment with cilostazol improves clinical outcome after endovascular therapy in hemodialysis patients with peripheral artery disease. J Cardiol 2016; 67(2): 199-204.
[http://dx.doi.org/10.1016/j.jjcc.2015.05.003] [PMID: 26074442]
[48]
de Boer IH, Group DER. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37(1): 24-30.
[http://dx.doi.org/10.2337/dc13-2113] [PMID: 24356594]
[49]
Wright RJ, Frier BM. Vascular disease and diabetes: Is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008; 24(5): 353-63.
[http://dx.doi.org/10.1002/dmrr.865] [PMID: 18461635]
[50]
Wang Z, Zhou C, Sun Y, Chen Y, Xue D. Let-7c-5p is involved in chronic kidney disease by targeting TGF- β signaling. BioMed Res Int 2020; 2020: 1-8.
[http://dx.doi.org/10.1155/2020/6960941] [PMID: 32626757]
[51]
Gholaminejad A, Abdul Tehrani H, Gholami Fesharaki M. Identification of candidate microRNA biomarkers in diabetic nephropathy: a meta-analysis of profiling studies. J Nephrol 2018; 31(6): 813-31.
[http://dx.doi.org/10.1007/s40620-018-0511-5] [PMID: 30019103]
[52]
Shan Q, Zheng G, Zhu A, et al. Epigenetic modification of miR-10a regulates renal damage by targeting CREB1 in type 2 diabetes mellitus. Toxicol Appl Pharmacol 2016; 306: 134-43.
[http://dx.doi.org/10.1016/j.taap.2016.06.010] [PMID: 27292126]
[53]
Perera CJ, Falasca M, Chari ST, et al. Role of pancreatic stellate cell-derived exosomes in pancreatic cancer-related diabetes: A novel hypothesis. Cancers 2021; 13(20): 5224.
[http://dx.doi.org/10.3390/cancers13205224] [PMID: 34680372]
[54]
Hourigan ST, Solly EL, Nankivell VA, et al. The regulation of miRNAs by reconstituted high-density lipoproteins in diabetes-impaired angiogenesis. Sci Rep 2018; 8(1): 13596.
[http://dx.doi.org/10.1038/s41598-018-32016-x] [PMID: 30206364]
[55]
Ebrahimi R, Bahiraee A, Niazpour F, Emamgholipour S, Meshkani R. The role of microRNAs in the regulation of insulin signaling pathway with respect to metabolic and mitogenic cascades: A review. J Cell Biochem 2019; 120(12): 19290-309.
[http://dx.doi.org/10.1002/jcb.29299] [PMID: 31364207]
[56]
Solly EL, Psaltis PJ, Bursill CA, Tan JTM. The role of mir-181c in mechanisms of diabetes-impaired angiogenesis: An emerging therapeutic target for diabetic vascular complications. Front Pharmacol 2021; 12: 718679.
[http://dx.doi.org/10.3389/fphar.2021.718679] [PMID: 34483928]
[57]
Johnson RJ, Raines EW, Floege J, et al. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 1992; 175(5): 1413-6.
[http://dx.doi.org/10.1084/jem.175.5.1413] [PMID: 1569407]
[58]
Kelly DJ, Gilbert R, Cox AJ, Soulis T, Jerums G, Cooper M. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol 2001; 12(10): 2098-107.
[http://dx.doi.org/10.1681/ASN.V12102098] [PMID: 11562408]
[59]
Nakagawa H, Sasahara M, Haneda M, Koya D, Hazama F, Kikkawa R. Immunohistochemical characterization of glomerular PDGF B-chain and PDGF β-receptor expression in diabetic rats. Diabetes Res Clin Pract 2000; 48(2): 87-98.
[http://dx.doi.org/10.1016/S0168-8227(99)00144-8] [PMID: 10802145]
[60]
Nakamura T, Fukui M, Ebihara I, et al. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 1993; 42(3): 450-6.
[http://dx.doi.org/10.2337/diab.42.3.450] [PMID: 8094359]
[61]
Inaba T, Ishibashi S, Gotoda T, et al. Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy. Diabetes 1996; 45(4): 507-12.
[http://dx.doi.org/10.2337/diab.45.4.507] [PMID: 8603774]
[62]
Matsuda M, Shikata K, Makino H, et al. Gene expression of PDGF and PDGF receptor in various forms of glomerulonephritis. Am J Nephrol 1997; 17(1): 25-31.
[http://dx.doi.org/10.1159/000169067] [PMID: 9057949]
[63]
Langham RG, Kelly DJ, Maguire J, Dowling JP, Gilbert RE, Thomson NM. Over-expression of platelet-derived growth factor in human diabetic nephropathy. Nephrol Dial Transplant 2003; 18(7): 1392-6.
[http://dx.doi.org/10.1093/ndt/gfg177] [PMID: 12808179]
[64]
Wei Q, Liu Y, Liu P, et al. MicroRNA-489 Induction by Hypoxia–Inducible Factor–1 Protects against Ischemic Kidney Injury. J Am Soc Nephrol 2016; 27(9): 2784-96.
[http://dx.doi.org/10.1681/ASN.2015080870] [PMID: 26975439]
[65]
Wang Z, Chang Y, Liu Y, et al. Inhibition of the lncRNA MIAT prevents podocyte injury and mitotic catastrophe in diabetic nephropathy. Mol Ther Nucleic Acids 2022; 28: 136-53.
[http://dx.doi.org/10.1016/j.omtn.2022.03.001] [PMID: 35402074]
[66]
Sui W, Dai Y, Huang Y, Lan H, Yan Q, Huang H. Microarray analysis of MicroRNA expression in acute rejection after renal transplantation. Transpl Immunol 2008; 19(1): 81-5.
[http://dx.doi.org/10.1016/j.trim.2008.01.007] [PMID: 18346642]
[67]
Cao N, Li X, Wang S-N, et al. Identification of potential biomarkers for clear cell renal cell carcinoma based on microRNA-mRNA pathway relationships. J Cancer Res Ther 2014; 10(7): 167.
[http://dx.doi.org/10.4103/0973-1482.145856] [PMID: 25450277]

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