{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:41:45Z","timestamp":1791380505565,"version":"4.3.3"},"reference-count":105,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the \u2018chronic hypoxia hypothesis\u2019, persistent inflammation, Transforming Growth Factor beta (TGF\u03b2), Janus Kinase\/Signal Transducers and Activators of Transcription (JAK\/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.<\/jats:p>","DOI":"10.3390\/ijms21238936","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T08:59:15Z","timestamp":1606294755000},"page":"8936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1587-5577","authenticated-orcid":false,"given":"Maria","family":"Fragiadaki","sequence":"first","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry &amp; Health, University of Sheffield, Sheffield S10 2RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Macleod","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry &amp; Health, University of Sheffield, Sheffield S10 2RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-5400","authenticated-orcid":false,"given":"Albert C. M.","family":"Ong","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry &amp; Health, University of Sheffield, Sheffield S10 2RX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv15","DOI":"10.1093\/ndt\/gfu017","article-title":"Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival--an analysis of data from the ERA-EDTA Registry","volume":"29","author":"Spithoven","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1056\/NEJM199307293290508","article-title":"Autosomal Dominant Polycystic Kidney Disease","volume":"329","author":"Gabow","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.bbadis.2011.06.012","article-title":"Fibrosis and progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)","volume":"1812","author":"Norman","year":"2011","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s40264-015-0327-3","article-title":"Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database","volume":"38","author":"Watkins","year":"2015","journal-title":"Drug Saf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1172\/JCI117251","article-title":"Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells","volume":"93","author":"Kagami","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.matbio.2011.07.004","article-title":"Interstitial fibrosis is associated with increased COL1A2 transcription in AA-injured renal tubular epithelial cells in vivo","volume":"30","author":"Fragiadaki","year":"2011","journal-title":"Matrix Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1098\/rstb.2004.1475","article-title":"Scar\u2013free healing: from embryonic mechanisms to adult therapeutic intervention","volume":"359","author":"Ferguson","year":"2004","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1242\/dev.112.2.651","article-title":"The extracellular matrix of lip wounds in fetal, neonatal and adult mice","volume":"112","author":"Whitby","year":"1991","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"European Polycystic Kidney Disease Consortium (1994). The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome. Cell, 78, 725.","DOI":"10.1016\/0092-8674(94)90137-6"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/ng0695-151","article-title":"The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains","volume":"10","author":"Hughes","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_11","first-page":"122","article-title":"The molecular genetics of autosomal dominant polycystic kidney disease","volume":"9","author":"Reeders","year":"1989","journal-title":"Semin. Nephrol."},{"key":"ref_12","first-page":"13","article-title":"Mapping the locus of autosomal dominant polycystic kidney disease: diagnostic application","volume":"35","author":"Reeders","year":"1989","journal-title":"Clin. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1126\/science.272.5266.1339","article-title":"PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein","volume":"272","author":"Mochizuki","year":"1996","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1097\/01.ASN.0000029587.47950.25","article-title":"The Polycystic Kidney Disease Proteins, Polycystin-1, Polycystin-2, Polaris, and Cystin, Are Co-Localized in Renal Cilia","volume":"13","author":"Yoder","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0697-179","article-title":"PKD1 interacts with PKD2 through a probable coiled-coil domain","volume":"16","author":"Qian","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/hmg\/6.9.1473","article-title":"An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection","volume":"6","author":"Watnick","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ki.2013.227","article-title":"Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families","volume":"85","author":"Paul","year":"2014","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1242\/dev.046045","article-title":"The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity","volume":"137","author":"Tran","year":"2010","journal-title":"Development"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1046\/j.1523-1755.2000.00205.x","article-title":"Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation","volume":"58","author":"Okada","year":"2000","journal-title":"Kidney Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.kint.2016.10.039","article-title":"STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease","volume":"91","author":"Fragiadaki","year":"2017","journal-title":"Kidney Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/ki.2013.13","article-title":"Cyst expansion and regression in a mouse model of polycystic kidney disease","volume":"83","author":"Salvatori","year":"2013","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1681\/ASN.2011010084","article-title":"Macrophages Promote Cyst Growth in Polycystic Kidney Disease","volume":"22","author":"Karihaloo","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/ki.2012.446","article-title":"Macrophages promote polycystic kidney disease progression","volume":"83","author":"Vivian","year":"2013","journal-title":"Kidney Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1681\/ASN.2018010074","article-title":"Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice","volume":"29","author":"Yang","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1681\/ASN.2018050518","article-title":"Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease","volume":"29","author":"Cassini","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1681\/ASN.2018080810","article-title":"Tissue-Resident Macrophages Promote Renal Cystic Disease","volume":"30","author":"Zimmerman","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Viau, A., Bienaim\u00e9, F., Lukas, K., Todkar, A.P., Knoll, M., Yakulov, T.A., Hofherr, A., Kretz, O., Helmst\u00e4dter, M., and Reichardt, W. (2018). Cilia-localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. EMBO J., 37.","DOI":"10.15252\/embj.201798615"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ki.1997.52","article-title":"Sites of erythropoietin production","volume":"51","author":"Maxwell","year":"1997","journal-title":"Kidney Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/j.1365-2613.2011.00775.x","article-title":"Epithelial-mesenchymal transition in renal fibrosis\u2014Evidence for and against","volume":"92","author":"Fragiadaki","year":"2011","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1172\/JCI72267","article-title":"Cellular and molecular mechanisms in kidney fibrosis","volume":"124","author":"Duffield","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30013","DOI":"10.1038\/srep30013","article-title":"Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models","volume":"6","author":"Ameku","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/ki.1996.10","article-title":"Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat","volume":"49","author":"Schaefer","year":"1996","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1159\/000013552","article-title":"Elevation of Serum Levels of Metalloproteinase-1, Tissue Inhibitor of Metalloproteinase-1 and Type IV Collagen, and Plasma Levels of Metalloproteinase-9 in Polycystic Kidney Disease","volume":"20","author":"Nakamura","year":"2000","journal-title":"Am. J. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.ekir.2019.03.011","article-title":"Urinary Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor\u2013Binding Protein 7 Do Not Correlate With Disease Severity in ADPKD Patients","volume":"4","author":"Dekker","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"ref_35","first-page":"74","article-title":"Progressive renal disease: the chronic hypoxia hypothesis","volume":"65","author":"Fine","year":"1998","journal-title":"Kidney Int. Suppl."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1159\/000499741","article-title":"Podocyte Injury in Autosomal Dominant Polycystic Kidney Disease","volume":"142","author":"Cebeci","year":"2019","journal-title":"Nephron"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/ndt\/gfp611","article-title":"Glomerular and proximal tubule cysts as early manifestations of Pkd1 deletion","volume":"25","author":"Ahrabi","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12174","DOI":"10.1073\/pnas.211191098","article-title":"Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene","volume":"98","author":"Boulter","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1038\/labinvest.2017.97","article-title":"Deletion of Pkd1 in renal stromal cells causes defects in the renal stromal compartment and progressive cystogenesis in the kidney","volume":"97","author":"Nie","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/micc.12022","article-title":"Polycystic kidneys have decreased vascular density: a micro-CT study","volume":"20","author":"Xu","year":"2013","journal-title":"Microcirculation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/sj.ki.5001725","article-title":"Evidence of angiogenesis and microvascular regression in autosomal-dominant polycystic kidney disease kidneys: A corrosion cast study","volume":"70","author":"Wei","year":"2006","journal-title":"Kidney Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1681\/ASN.2008040435","article-title":"Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia\/reperfusion","volume":"20","author":"Bastos","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"cm8","DOI":"10.1126\/stke.4072007cm8","article-title":"Hypoxia-Inducible Factor 1 (HIF-1) Pathway","volume":"2007","author":"Semenza","year":"2007","journal-title":"Sci. STKE"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.kint.2018.06.008","article-title":"HIF-1\u03b1 promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease","volume":"94","author":"Kraus","year":"2018","journal-title":"Kidney Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"830","DOI":"10.2353\/ajpath.2007.060455","article-title":"Involvement of Hypoxia-Inducible Transcription Factors in Polycystic Kidney Disease","volume":"170","author":"Bernhardt","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"F1235","DOI":"10.1152\/ajprenal.00348.2010","article-title":"Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) and autophagy in polycystic kidney disease (PKD)","volume":"300","author":"Belibi","year":"2011","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0092-8674(01)00507-4","article-title":"C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation","volume":"107","author":"Epstein","year":"2001","journal-title":"Cell"},{"key":"ref_48","first-page":"271","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/ki.2013.418","article-title":"Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst\u2013forming epithelial cells","volume":"85","author":"Buchholz","year":"2014","journal-title":"Kidney Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.kint.2020.02.008","article-title":"Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for autosomal dominant polycystic kidney disease","volume":"98","author":"Magayr","year":"2020","journal-title":"Kidney Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-18104-5","article-title":"Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo","volume":"11","author":"Cabrita","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0092-8674(02)00716-X","article-title":"PKD1 Induces p21waf1 and Regulation of the Cell Cycle via Direct Activation of the JAK-STAT Signaling Pathway in a Process Requiring PKD2","volume":"109","author":"Bhunia","year":"2002","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7985","DOI":"10.1073\/pnas.1103816108","article-title":"Polycystin-1 regulates STAT activity by a dual mechanism","volume":"108","author":"Talbot","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"111922","DOI":"10.18632\/oncotarget.22952","article-title":"IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma","volume":"8","author":"Zhao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e28975","DOI":"10.4161\/jkst.28975","article-title":"STAT3 and epithelial\u2013mesenchymal transitions in carcinomas","volume":"3","author":"Wendt","year":"2014","journal-title":"JAK STAT"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1007\/s00109-019-01852-3","article-title":"Characterisation of transcription factor profiles in polycystic kidney disease (PKD): identification and validation of STAT3 and RUNX1 in the injury\/repair response and PKD progression","volume":"97","author":"Formica","year":"2019","journal-title":"J. Mol. Med. (Berl)"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1681\/ASN.2019090959","article-title":"Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease","volume":"31","author":"Viau","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1038\/s41598-019-41106-3","article-title":"Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis","volume":"9","author":"Patera","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e129","DOI":"10.1159\/000094963","article-title":"A critical look at growth factors and epithelial-to-mesenchymal transition in the adult kidney. Interrelationships between growth factors that regulate EMT in the adult kidney","volume":"104","author":"Wahab","year":"2006","journal-title":"Nephron Exp. Nephrol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1172\/JCI0215518","article-title":"Evidence that fibroblasts derive from epithelium during tissue fibrosis","volume":"110","author":"Iwano","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3349\/ymj.2009.50.1.105","article-title":"TGF-beta Mediated Epithelial-Mesenchymal Transition in Autosomal Dominant Polycystic Kidney Disease","volume":"50","author":"Chea","year":"2009","journal-title":"Yonsei Med. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.yexcr.2017.04.001","article-title":"Ouabain promotes partial epithelial to mesenchymal transition (EMT) changes in human autosomal dominant polycystic kidney disease (ADPKD) cells","volume":"355","author":"Venugopal","year":"2017","journal-title":"Exp. Cell Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"F511","DOI":"10.1152\/ajprenal.00038.2010","article-title":"Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease","volume":"300","author":"Togawa","year":"2011","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"23337","DOI":"10.1074\/jbc.M700194200","article-title":"Fibroblasts Derive from Hepatocytes in Liver Fibrosis via Epithelial to Mesenchymal Transition","volume":"282","author":"Zeisberg","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/nm888","article-title":"BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury","volume":"9","author":"Zeisberg","year":"2003","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1101\/gad.8.2.133","article-title":"The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms","volume":"8","author":"Kingsley","year":"1994","journal-title":"Genes Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.bbadis.2009.06.004","article-title":"TGF-beta and fibrosis in different organs\u2014Molecular pathway imprints","volume":"1792","author":"Pohlers","year":"2009","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1016\/S0140-6736(09)60705-4","article-title":"Wound healing: From embryos to adults and back again","volume":"373","author":"Tredget","year":"2009","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jbmt.2008.04.031","article-title":"Myofibroblasts work best under stress","volume":"13","author":"Wipff","year":"2009","journal-title":"J. Bodyw. Mov. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"228","DOI":"10.7150\/ijbs.8.228","article-title":"The Pro-inflammatory Role of TGFbeta1: A Paradox?","volume":"8","author":"Han","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s42255-019-0102-3","article-title":"Endothelial TGF-beta signalling drives vascular inflammation and atherosclerosis","volume":"1","author":"Chen","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/path.2734","article-title":"Elevated TGFbeta -Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease","volume":"222","author":"Hassane","year":"2010","journal-title":"J. Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1093\/hmg\/ddp165","article-title":"Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks","volume":"18","author":"Song","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-56995-7","article-title":"A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2\u2212\/\u2212 phenotype","volume":"10","author":"Metzner","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/j.yexcr.2012.03.021","article-title":"Transforming growth factor- beta inhibits cystogenesis in human autosomal dominant polycystic kidney epithelial cells","volume":"318","author":"Elberg","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1681\/ASN.2015030287","article-title":"Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease","volume":"27","author":"Leonhard","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_78","first-page":"64","article-title":"The impact of microRNAs on protein output","volume":"455","author":"Baek","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1681\/ASN.2010080841","article-title":"The pro-apoptotic protein Bim is a microRNA target in kidney progenitors","volume":"22","author":"Ho","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/ki.2010.385","article-title":"Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney","volume":"79","author":"Nagalakshmi","year":"2011","journal-title":"Kidney Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1681\/ASN.2012030321","article-title":"MicroRNAs Regulate Renal Tubule Maturation through Modulation of Pkd1","volume":"23","author":"Patel","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1681\/ASN.2013040390","article-title":"MicroRNA-17~92 Is Required for Nephrogenesis and Renal Function","volume":"25","author":"Marrone","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1681\/ASN.2008020233","article-title":"Podocyte-Specific Deletion of Dicer Alters Cytoskeletal Dynamics and Causes Glomerular Disease","volume":"19","author":"Harvey","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1681\/ASN.2009090964","article-title":"The MicroRNA-Processing Enzyme Dicer Maintains Juxtaglomerular Cells","volume":"21","author":"Lopez","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Pandey, P., Brors, B., Srivastava, P.K., Bott, A., Boehn, S.N., Gr\u00f6ne, H.-J., and Gretz, N. (2008). Microarray-based approach identifies microRNAs and their target functional patterns in polycystic kidney disease. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-624"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1056\/NEJMoa054341","article-title":"Volume Progression in Polycystic Kidney Disease","volume":"354","author":"Grantham","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1681\/ASN.2012070650","article-title":"Type of PKD1 Mutation Influences Renal Outcome in ADPKD","volume":"24","author":"Gall","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Cardenas, C.L.L., Henaoui, I.S., Courcot, E., Roderburg, C., Cauffiez, C., Aubert, S., Copin, M.-C., Wallaert, B., Glowacki, F., and Dewaeles, E. (2013). miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003291"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ben-Dov, I.Z., Tan, Y.-C., Morozov, P., Wilson, P.D., Rennert, H., Blumenfeld, J.D., and Tuschl, T. (2014). Urine MicroRNA as Potential Biomarkers of Autosomal Dominant Polycystic Kidney Disease Progression: Description of miRNA Profiles at Baseline. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086856"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Magayr, T., Streets, A., and Ong, A. (2019). Global microrna profiling in human urinary exosomes reveals new disease biomarkers and cellular pathways for autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transplant., 34.","DOI":"10.1093\/ndt\/gfz107.FO026"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1096\/fj.201800563RR","article-title":"Impact of miR-192 and miR-194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease","volume":"33","author":"Kim","year":"2019","journal-title":"FASEB J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"9628","DOI":"10.1158\/0008-5472.CAN-05-2352","article-title":"A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation","volume":"65","author":"Hayashita","year":"2005","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"10765","DOI":"10.1073\/pnas.1301693110","article-title":"miR-17 similar to 92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease","volume":"110","author":"Patel","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"14395","DOI":"10.1038\/ncomms14395","article-title":"microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism","volume":"8","author":"Hajarnis","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-11918-y","article-title":"Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-38566-y","article-title":"Anti-microRNA screen uncovers miR-17 family within miR-17 similar to 92 cluster as the primary driver of kidney cyst growth","volume":"9","author":"Yheskel","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1172\/JCI43604","article-title":"Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice","volume":"120","author":"Patrick","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"121ra18","DOI":"10.1126\/scitranslmed.3003205","article-title":"MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways","volume":"4","author":"Chau","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Glowacki, F., Savary, G., Gnemmi, V., Buob, D., Van Der Hauwaert, C., Lo-Guidice, J.-M., Bouy\u00e9, S., Hazzan, M., Pottier, N., and Perrais, M. (2013). Increased Circulating miR-21 Levels Are Associated with Kidney Fibrosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058014"},{"key":"ref_100","first-page":"srep02038","article-title":"MiR-21\/Smad 7 signaling determines TGF-beta 1-induced CAF formation","volume":"3","author":"Li","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"27209","DOI":"10.1038\/srep27209","article-title":"miR-21-5p renal expression is associated with fibrosis and renal survival in patients with IgA nephropathy","volume":"6","author":"Hennino","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"10144","DOI":"10.1073\/pnas.1103735108","article-title":"Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis","volume":"108","author":"Ma","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1681\/ASN.2010111168","article-title":"Smad3-Mediated Upregulation of miR-21 Promotes Renal Fibrosis","volume":"22","author":"Zhong","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/onc.2011.222","article-title":"Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan\/CD44-activated head and neck squamous cell carcinoma cells","volume":"31","author":"Bourguignon","year":"2012","journal-title":"Oncogene"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1681\/ASN.2015060634","article-title":"MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease","volume":"27","author":"Lakhia","year":"2016","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/8936\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:37:07Z","timestamp":1760179027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/8936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,25]]},"references-count":105,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21238936"],"URL":"https:\/\/doi.org\/10.3390\/ijms21238936","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,25]]}}}