Epithelial–mesenchymal transition in organ fibrosis development: current understanding and treatment strategies

Abstract

Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial–mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.

Keywords

EMT / Fibrosis / TGF-β / Smad / HDAC inhibitors / TGF-β antibody / Organ fibrosis / Senescence / Extracellular matrix

References

[1] Olson AL, Gifford AH, Inase N, Fernandez Perez ER, Suda T. The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur Respir Rev. 2018; 27: 180077.

[2] Ng JK, Li PK. Chronic kidney disease epidemic: how do we deal with it? Nephrology (Carlton). 2018; 23: 116-20.

[3] Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, et al. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2020; 395: 709-33.

[4] Nunes C, Pereira AM, Morais-Almeida M. Asthma costs and social impact. Asthma Res Pract. 2017; 3: 1.

[5] Duarte VM, McGrath CL, Shapiro NL, Bhattacharrya N. Healthcare costs of acute and chronic tonsillar conditions in the pediatric population in the United States. Int J Pediatr Otorhinolaryngol. 2015; 79: 921-5.

[6] Rockey DC, Bell PD, Hill JA. Fibrosis-a common pathway to organ injury and failure. N Engl J Med. 2015; 372: 1138-49.

[7] LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013; 19: 1047-53.

[8] Plikus MV, Guerrero-Juarez CF, Ito M, Li YR, Dedhia PH, Zheng Y, et al. Regeneration of fat cells from myofibroblasts during wound healing. Science. 2017; 355: 748-52.

[9] Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W, Atkins RC, et al. Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int. 1999; 56: 1455-67.

[10] Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016; 166: 21-45.

[11] Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A, Arevalo M, et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015; 21: 989-97.

[12] Di Gregorio J, Robuffo I, Spalletta S, Giambuzzi G, De Iuliis V, Toniato E, et al. The epithelial-to-mesenchymal transition as a possible therapeutic target in fibrotic disorders. Front Cell Dev Biol. 2020; 8: 607483.

[13] Pan B, Liu G, Jiang Z, Zheng D. Regulation of renal fibrosis by macrophage polarization. Cell Physiol Biochem. 2015; 35: 1062-9.

[14] Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009; 1: 303-14.

[15] Liu B, Ding F, Hu D, Zhou Y, Long C, Shen L, et al. Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro. Stem Cell Res Ther. 2018; 9: 7.

[16] Qi R, Wang J, Jiang Y, Qiu Y, Xu M, Rong R, et al. Snai1-induced partial epithelial-mesenchymal transition orchestrates p53-p21-mediated G2/M arrest in the progression of renal fibrosis via NF-kappaB-mediated inflammation. Cell Death Dis. 2021; 12: 44.

[17] Cong LH, Li T, Wang H, Wu YN, Wang SP, Zhao YY, et al. IL-17A-producing T cells exacerbate fine particulate matter-induced lung inflammation and fibrosis by inhibiting PI3K/Akt/mTOR-mediated autophagy. J Cell Mol Med. 2020; 24: 8532-44.

[18] Du R, Xia L, Ning X, Liu L, Sun W, Huang C, et al. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell. 2014; 25: 2650-9.

[19] Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7: re8.

[20] Wei X, Zhu X, Jiang L, Huang X, Zhang Y, Zhao D, et al. Recent advances in understanding the role of hypoxia-inducible factor 1alpha in renal fibrosis. Int Urol Nephrol. 2020; 52: 1287-95.

[21] Zhang M, Liu S, Guan E, Liu H, Dong X, Hao Y, et al. Hyperbaric oxygen therapy can ameliorate the EMT phenomenon in keloid tissue. Medicine (Baltimore). 2018; 97: e11529.

[22] Sosa Peña MP, Lopez-Soler R, Melendez JA. Senescence in chronic allograft nephropathy. Am J Physiol Renal Physiol. 2018; 315: F880-9.

[23] Vigneron A, Vousden KH. p53, ROS and senescence in the control of aging. Aging (Albany NY). 2010; 2: 471-4.

[24] Shimizu H, Bolati D, Adijiang A, Enomoto A, Nishijima F, Dateki M, et al. Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. Am J Physiol Cell Physiol. 2010; 299: C1110-7.

[25] Li D, Pei X, Qin X, Liu X, Li C, Li L, et al. Olaquindox-induced liver damage involved the crosstalk of oxidative stress and p53 in vivo and in vitro. Oxidative Med Cell Longev. 2020; 2020: 1-18.

[26] Gonzalez-Gonzalez FJ, Chandel NS, Jain M, Budinger GRS. Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl Res. 2017; 190: 61-8.

[27] Muthuramalingam K, Cho M, Kim Y. Cellular senescence and EMT crosstalk in bleomycin-induced pathogenesis of pulmonary fibrosis-an in vitro analysis. Cell Biol Int. 2020; 44: 477-87.

[28] Kong D, Zhang Z, Chen L, Huang W, Zhang F, Wang L, et al. Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy. Redox Biol. 2020; 36: 101600.

[29] Jolly MK, Ward C, Eapen MS, Myers S, Hallgren O, Levine H, et al. Epithelial-mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease. Dev Dyn. 2018; 247: 346-58.

[30] Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, et al. New insights into TGF-beta/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018; 292: 76-83.

[31] Chen L, Yang T, Lu DW, Zhao H, Feng YL, Chen H, et al. Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomed Pharmacother. 2018; 101: 670-81.

[32] Yang F, Huang XR, Chung AC, Hou CC, Lai KN, Lan HY. Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol. 2010; 221: 390-401.

[33] Yang F, Chung AC, Huang XR, Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and-independent Smad pathways: the role of Smad3. Hypertension. 2009; 54: 877-84.

[34] Wang YC, Liu JS, Tang HK, Nie J, Zhu JX, Wen LL, et al. miR221 targets HMGA2 to inhibit bleomycininduced pulmonary fibrosis by regulating TGFbeta1/Smad3-induced EMT. Int J Mol Med. 2016; 38: 1208-16.

[35] Wang Y, Zhang X, Mao Y, Liang L, Liu L, Peng W, et al. Smad2 and Smad3 play antagonistic roles in high glucose-induced renal tubular fibrosis via the regulation of SnoN. Exp Mol Pathol. 2020; 113: 104375.

[36] Loeffler I, Liebisch M, Allert S, Kunisch E, Kinne RW, Wolf G. FSP1-specific SMAD2 knockout in renal tubular, endothelial, and interstitial cells reduces fibrosis and epithelial-to-mesenchymal transition in murine STZ-induced diabetic nephropathy. Cell Tissue Res. 2018; 372: 115-33.

[37] Gervasi M, Bianchi-Smiraglia A, Cummings M, Zheng Q, Wang D, Liu S, et al. JunB contributes to Id2 repression and the epithelial-mesenchymal transition in response to transforming growth factor-beta. J Cell Biol. 2012; 196: 589-603.

[38] Xiao Z, Chen C, Meng T, Zhang W, Zhou Q. Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-beta pathway on matrix metalloproteinase 7. Exp Biol Med (Maywood). 2016; 241: 140-6.

[39] Yan X, Chen YG. Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling. Biochem J. 2011; 434: 1-10.

[40] Yan X, Liao H, Cheng M, Shi X, Lin X, Feng XH, et al. Smad7 protein interacts with receptor-regulated Smads (R-Smads) to inhibit transforming growth factor-beta (TGF-beta)/Smad Signaling. J Biol Chem. 2016; 291: 382-92.

[41] Lien EC, Dibble CC, Toker A. PI3K signaling in cancer: beyond AKT. Curr Opin Cell Biol. 2017; 45: 62-71.

[42] Zhang Z, Yao L, Yang J, Wang Z, Du G. PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia (review). Mol Med Rep. 2018; 18: 3547-54.

[43] Wang Z, Chen Z, Li B, Zhang B, Du Y, Liu Y, et al. Curcumin attenuates renal interstitial fibrosis of obstructive nephropathy by suppressing epithelial-mesenchymal transition through inhibition of the TLR4/NF-small ka, CyrillicB and PI3K/AKT signaling pathways. Pharm Biol. 2020; 58: 828-37.

[44] Lu Q, Wang WW, Zhang MZ, Ma ZX, Qiu XR, Shen M, et al. ROS induces epithelial-mesenchymal transition via the TGF-beta1/PI3K/Akt/mTOR pathway in diabetic nephropathy. Exp Ther Med. 2019; 17: 835-46.

[45] Wang J, Zhu H, Huang L, Zhu X, Sha J, Li G, et al. Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways. Exp Mol Pathol. 2019; 111: 104296.

[46] Zhou T, Luo M, Cai W, Zhou S, Feng D, Xu C, et al. Runt-related transcription factor 1 (RUNX1) promotes TGF-β-induced renal tubular epithelial-to-mesenchymal transition (EMT) and renal fibrosis through the PI3K subunit p110δ. EBioMedicine. 2018; 31: 217-25.

[47] Zhu FQ, Chen MJ, Zhu M, Zhao RS, Qiu W, Xu X, et al. Curcumin suppresses epithelial-mesenchymal transition of renal tubular epithelial cells through the inhibition of Akt/mTOR pathway. Biol Pharm Bull. 2017; 40: 17-24.

[48] Shin JH, Kim KM, Jeong JU, Shin JM, Kang JH, Bang K, et al. Nrf2-Heme Oxygenase-1 attenuates high-glucose-induced epithelial-to-mesenchymal transition of renal tubule cells by inhibiting ROS-mediated PI3K/Akt/GSK-3βSignaling. J Diabetes Res. 2019; 2019: 1-8.

[49] Zhang X, Liang D, Fan J, Lian X, Zhao Y, Wang X, et al. Zinc attenuates Tubulointerstitial fibrosis in diabetic nephropathy via inhibition of HIF through PI-3K Signaling. Biol Trace Elem Res. 2016; 173: 372-83.

[50] Geng XQ, Ma A, He JZ, Wang L, Jia YL, Shao GY, et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways. Acta Pharmacol Sin. 2020; 41: 670-7.

[51] Wang S, Zhou Y, Zhang Y, He X, Zhao X, Zhao H, et al. Roscovitine attenuates renal interstitial fibrosis in diabetic mice through the TGF-β1/p38 MAPK pathway. Biomed Pharmacother. 2019; 115: 108895.

[52] Zhang X, Liang D, Chi ZH, Chu Q, Zhao C, Ma RZ, et al. Effect of zinc on high glucose-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells. Int J Mol Med. 2015; 35: 1747-54.

[53] Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronsh-tam A, Clements JL, et al. Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science. 2008; 320: 667-70.

[54] Gao F, Wang Y, Li S, Wang Z, Liu C, Sun D. Inhibition of p38 mitogen-activated protein kinases attenuates renal interstitial fibrosis in a murine unilateral ureteral occlusion model. Life Sci. 2016; 167: 78-84.

[55] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15: 178-96.

[56] Park JH, Park B, Park KK. Suppression of hepatic epithelial-to-mesenchymal transition by Melittin via blocking of TGf β/Smad and MAPK-JNK Signaling pathways. Toxins (Basel). 2017; 9: 138.

[57] Li Z, Liu X, Tian F, Li J, Wang Q, Gu C. MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway. Clin Sci (Lond). 2018; 132: 2339-55.

[58] Ebelt ND, Cantrell MA, Van Den Berg CL. C-Jun N-terminal kinases mediate a wide range of targets in the metastatic Cascade. Genes Cancer. 2013; 4: 378-87.

[59] Wu Y, Wang L, Deng D, Zhang Q, Liu W. Renalase protects against renal fibrosis by inhibiting the activation of the ERK Signaling pathways. Int J Mol Sci. 2017; 18: 855.

[60] Wang Y, Guo YF, Fu GP, Guan C, Zhang X, Yang DG, et al. Protective effect of miRNA-containing extracellular vesicles derived from mesenchymal stromal cells of old rats on renal function in chronic kidney disease. Stem Cell Res Ther. 2020; 11: 274.

[61] Xiao H, Shen HY, Liu W, Xiong RP, Li P, Meng G, et al. Adenosine A2A receptor: a target for regulating renal interstitial fibrosis in obstructive nephropathy. PLoS One. 2013; 8: e60173.

[62] Antonioli L, Blandizzi C, Pacher P, Hasko G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer. 2013; 13: 842-57.

[63] Zuccarini M, Giuliani P, Buccella S, Di Liberto V, Mudo G, Belluardo N, et al. Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells. Purinergic Signal. 2017; 13: 429-42.

[64] Tan RJ, Zhou D, Zhou L, Liu Y. Wnt/β-catenin signaling and kidney fibrosis. Kidney Int Suppl (2011). 2014; 4: 84-90.

[65] Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 2010; 21: 212-22.

[66] Hwang I, Seo EY, Ha H. Wnt/beta-catenin signaling: a novel target for therapeutic intervention of fibrotic kidney disease. Arch Pharm Res. 2009; 32: 1653-66.

[67] Schinner S, Willenberg HS, Schott M, Scherbaum WA. Pathophysiological aspects of Wnt-signaling in endocrine disease. Eur J Endocrinol. 2009; 160: 731-7.

[68] Kim MK, Maeng YI, Sung WJ, Oh HK, Park JB, Yoon GS, et al. The differential expression of TGF-β1, ILK and wnt signaling inducing epithelial to mesenchymal transition in human renal fibrogenesis: an immunohistochemical study. Int J Clin Exp Pathol. 2013; 6: 1747-58.

[69] Yamamizu K, Matsunaga T, Uosaki H, Fukushima H, Katayama S, Hiraoka-Kanie M, et al. Convergence of notch and beta-catenin signaling induces arterial fate in vascular progenitors. J Cell Biol. 2010; 189: 325-38.

[70] Jeong MH, Kim HR, Park YJ, Chung KH. Akt and notch pathways mediate polyhexamethylene guanidine phosphate-induced epithelial-mesenchymal transition via ZEB2. Toxicol Appl Pharmacol. 2019; 380: 114691.

[71] Li T, Yang X, Xin S, Cao Y, Wang N. Paraquat poisoning induced pulmonary epithelial mesenchymal transition through Notch1 pathway. Sci Rep. 2017; 7: 924.

[72] Du R, Sun W, Xia L, Zhao A, Yu Y, Zhao L, et al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the notch signaling pathway in tubular epithelial cells. PLoS One. 2012; 7: e30771.

[73] Li B, Zhu C, Dong L, Qin J, Xiang W, Davidson AJ, et al. ADAM10 mediates ectopic proximal tubule development and renal fibrosis through notch signaling. J Pathol. 2020; 252: 274-89.

[74] Marquez-Exposito L, Lavoz C, Rodrigues-Diez RR, Rayego-Mateos S, Orejudo M, Cantero-Navarro E, et al. Gremlin regulates tubular epithelial to mesenchymal transition via VEGFR2: potential role in renal fibrosis. Front Pharmacol. 2018; 9: 1195.

[75] Hultgren NW, Fang JS, Ziegler ME, Ramirez RN, Phan DTT, Hatch MMS, et al. Slug regulates the Dll4-notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nat Commun. 2020; 11: 5400.

[76] Rhyu DY, Yang Y, Ha H, Lee GT, Song JS, Uh ST, et al. Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol. 2005; 16: 667-75.

[77] Liu Q, Zhang Y, Mao H, Chen W, Luo N, Zhou Q, et al. A crosstalk between the Smad and JNK signaling in the TGF-beta-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells. PLoS One. 2012; 7: e32009.

[78] van der Velden JL, Guala AS, Leggett SE, Sluimer J, Badura EC, Janssen-Heininger YM. Induction of a mesenchymal expression program in lung epithelial cells by wingless protein (Wnt)/β-catenin requires the presence of c-Jun N-terminal kinase-1 (JNK1). Am J Respir Cell Mol Biol. 2012; 47: 306-14.

[79] Li N, Jia T, Li YR. LncRNA NEAT1 accelerates the occurrence and development of diabetic nephropathy by sponging miR-23c. Eur Rev Med Pharmacol Sci. 2020; 24: 1325-37.

[80] Zhang Y, Yao XH, Wu Y, Cao GK, Han D. LncRNA NEAT1 regulates pulmonary fibrosis through miR-9-5p and TGF-β signaling pathway. Eur Rev Med Pharmacol Sci. 2020; 24: 8483-92.

[81] Zheng J, Yu F, Dong P, Wu L, Zhang Y, Hu Y, et al. Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152. Oncotarget. 2016; 7: 62886-97.

[82] Liu L, Zou J, Guan Y, Zhang Y, Zhang W, Zhou X, et al. Blocking the histone lysine 79 methyltransferase DOT1L alleviates renal fibrosis through inhibition of renal fibroblast activation and epithelial-mesenchymal transition. FASEB J. 2019; 33: 11941-58.

[83] Nagaraja SS, Subramanian U, Nagarajan D. Radiation-induced H3K9 methylation on E-cadherin promoter mediated by ROS/snail axis : role of G9a signaling during lung epithelial-mesenchymal transition. Toxicol in Vitro. 2021; 70: 105037.

[84] Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011; 43: 811-22.

[85] Hu L, Yu Y, Huang H, Fan H, Hu L, Yin C, et al. Epigenetic regulation of interleukin 6 by histone acetylation in macrophages and its role in Paraquat-induced pulmonary fibrosis. Front Immunol. 2016; 7: 696.

[86] Rout-Pitt N, Farrow N, Parsons D, Donnelley M. Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology. Respir Res. 2018; 19: 136.

[87] Yang ZC, Yi MJ, Ran N, Wang C, Fu P, Feng XY, et al. Transforming growth factor-beta1 induces bronchial epithelial cells to mesenchymal transition by activating the snail pathway and promotes airway remodeling in asthma. Mol Med Rep. 2013; 8: 1663- 8.

[88] Yamaguchi M, Hirai S, Tanaka Y, Sumi T, Miyajima M, Mishina T, et al. Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis. Lab Investig. 2017; 97: 232-42.

[89] Zolak JS, Jagirdar R, Surolia R, Karki S, Oliva O, Hock T, et al. Pleural mesothelial cell differentiation and invasion in fibrogenic lung injury. Am J Pathol. 2013; 182: 1239-47.

[90] Rowe RG, Lin Y, Shimizu-Hirota R, Hanada S, Neilson EG, Greenson JK, et al. Hepatocyte-derived Snail1 propagates liver fibrosis progression. Mol Cell Biol. 2011; 31: 2392-403.

[91] Park JH, Yoon J, Lee KY, Park B. Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGFbeta/Smad and ERK-MAPK signaling pathways. Biochimie. 2015; 113: 26-34.

[92] Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology. 2010; 51: 1027-36.

[93] Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 2008; 118: 3331-42.

[94] Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology. 2010; 139: 987-98.

[95] Iwaisako K, Jiang C, Zhang M, Cong M, Moore-Morris TJ, Park TJ, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A. 2014; 111: E3297-305.

[96] Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology. 2009; 50: 2007-13.

[97] Michelotti GA, Xie G, Swiderska M, Choi SS, Karaca G, Kruger L, et al. Smoothened is a master regulator of adult liver repair. J Clin Invest. 2013; 123: 2380-94.

[98] Luo GH, Lu YP, Yang L, Song J, Shi YJ, Li YP. Epithelial to mesenchymal transformation in tubular epithelial cells undergoing anoxia. Transplant Proc. 2008; 40: 2800-3.

[99] Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002; 110: 341-50.

[100] Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015; 21: 998-1009.

[101] Wang X, Gao Y, Tian N, Wang T, Shi Y, Xu J, et al. Astragaloside IV inhibits glucose-induced epithelial-mesenchymal transition of podocytes through autophagy enhancement via the SIRT-NF-κB p65 axis. Sci Rep. 2019; 9: 323.

[102] Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol. 2008; 19: 2282-7.

[103] Lovisa S, Fletcher-Sananikone E, Sugimoto H, Hensel J, Lahiri S, Hertig A, et al. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis. Sci Signal. 2020; 13, eaaz2597.

[104] Miao H, Cao G, Wu XQ, Chen YY, Chen DQ, Chen L, et al. Identification of endogenous 1-aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation. Br J Pharmacol. 2020; 177: 3415-35.

[105] Feng YL, Cao G, Chen DQ, Vaziri ND, Chen L, Zhang J, et al. Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease. Cell Mol Life Sci. 2019; 76: 4961-78.

[106] Chen L, Chen DQ, Liu JR, Zhang J, Vaziri ND, Zhuang S, et al. Unilateral ureteral obstruction causes gut microbial dysbiosis and metabolome disorders contributing to tubulointerstitial fibrosis. Exp Mol Med. 2019; 51: 1-18.

[107] Chen DQ, Cao G, Chen H, Argyopoulos CP, Yu H, Su W, et al. Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan. Nat Commun. 2019; 10: 1476.

[108] Wenxiu J, Mingyue Y, Fei H, Yuxin L, Mengyao W, Chenyang L, et al. Effect and mechanism of TL1A expression on epithelial-mesenchymal transition during chronic colitis-related intestinal fibrosis. Mediat Inflamm. 2021; 2021: 1-21.

[109] Scharl M, Weber A, Furst A, Farkas S, Jehle E, Pesch T, et al. Potential role for SNAIL family transcription factors in the etiology of Crohn’s disease-associated fistulae. Inflamm Bowel Dis. 2011; 17: 1907-16.

[110] Ortiz-Masia D, Gisbert-Ferrandiz L, Bauset C, Coll S, Mamie C, Scharl M, et al. Succinate activates EMT in intestinal epithelial cells through SUCNR1: a novel protagonist in fistula development. Cell. 2020; 9: 1104.

[111] Strippoli R, Moreno-Vicente R, Battistelli C, Cicchini C, Noce V, Amicone L, et al. Molecular mechanisms underlying peritoneal EMT and fibrosis. Stem Cells Int. 2016; 2016: 1-11.

[112] Aroeira LS, Aguilera A, Sanchez-Tomero JA, Bajo MA, del Peso G, Jimenez-Heffernan JA, et al. Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions. J Am Soc Nephrol. 2007; 18: 2004-13.

[113] Kang DH. Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis. Kidney Res Clin Pract. 2020; 39: 136-44.

[114] Blom JN, Feng Q. Cardiac repair by epicardial EMT: current targets and a potential role for the primary cilium. Pharmacol Ther. 2018; 186: 114-29.

[115] Hao YM, Yuan HQ, Ren Z, Qu SL, Liu LS, Dang H, et al. Endothelial to mesenchymal transition in atherosclerotic vascular remodeling. Clin Chim Acta. 2019; 490: 34-8.

[116] Duan J, Gherghe C, Liu D, Hamlett E, Srikantha L, Rodgers L, et al. Wnt1/betacatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J. 2012; 31: 429-42.

[117] Li Y, Lui KO, Zhou B. Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol. 2018; 15: 445-56.

[118] Lovisa S, Zeisberg M, Kalluri R. Partial epithelial-to-mesenchymal transition and other new mechanisms of kidney fibrosis. Trends Endocrinol Metab. 2016; 27: 681-95.

[119] Yan XL, Wang YY, Yu ZF, Tian MM, Li H. Peroxisome proliferator-activated receptor-gamma activation attenuates diabetic cardiomyopathy via regulation of the TGF-β/ERK pathway and epithelial-to-mesenchymal transition. Life Sci. 2018; 213: 269-78.

[120] Kuwahara H, Tosa M, Egawa S, Murakami M, Mohammad G, Ogawa R. Examination of epithelial mesenchymal transition in keloid tissues and possibility of keloid therapy target. Plast Reconstr Surg Glob Open. 2016; 4: e1138.

[121] Bale S, Pulivendala G, Godugu C. Withaferin a attenuates bleomycin-induced scleroderma by targeting FoxO3a and NF-κβ signaling: connecting fibrosis and inflammation. Biofactors. 2018; 44: 507-17.

[122] Takahashi M, Akamatsu H, Yagami A, Hasegawa S, Ohgo S, Abe M, et al. Epithelial-mesenchymal transition of the eccrine glands is involved in skin fibrosis in morphea. J Dermatol. 2013; 40: 720-5.

[123] Du L, Hao M, Li C, Wu W, Wang W, Ma Z, et al. Quercetin inhibited epithelial mesenchymal transition in diabetic rats, high-glucose-cultured lens, and SRA01/04 cells through transforming growth factor-β2/phosphoinositide 3-kinase/Akt pathway. Mol Cell Endocrinol. 2017; 452: 44-56.

[124] Saika S, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, Sumioka T, et al. Epithelial-mesenchymal transition as a therapeutic target for prevention of ocular tissue fibrosis. Endocr Metab Immune Disord Drug Targets. 2008; 8: 69-76.

[125] Gu TT, Chen TY, Yang YZ, Zhao XJ, Sun Y, Li TS, et al. Pterostilbene alleviates fructose-induced renal fibrosis by suppressing TGF-β1/TGF-β type I receptor/Smads signaling in proximal tubular epithelial cells. Eur J Pharmacol. 2019; 842: 70-8.

[126] Zhang X, Lu H, Xie S, Wu C, Guo Y, Xiao Y, et al. Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation-related signaling pathways. Br J Pharmacol. 2019; 176: 4745-59.

[127] Zhao JL, Zhang T, Shao X, Zhu JJ, Guo MZ. Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis. BMC Complement Altern Med. 2019; 19: 280.

[128] Chen H, Yang T, Wang MC, Chen DQ, Yang Y, Zhao YY. Novel RAS inhibitor 25-O-methylalisol F attenuates epithelial-to-mesenchymal transition and tubulo-interstitial fibrosis by selectively inhibiting TGF-β-mediated Smad3 phosphorylation. Phytomedicine. 2018; 42: 207-18.

[129] Wang M, Chen DQ, Chen L, Liu D, Zhao H, Zhang ZH, et al. Novel RAS inhibitors Poricoic acid ZG and Poricoic acid ZH attenuate renal fibrosis via a Wnt/β-catenin pathway and targeted phosphorylation of smad3 Signaling. J Agric Food Chem. 2018; 66: 1828-42.

[130] Wang M, Chen DQ, Chen L, Cao G, Zhao H, Liu D, et al. Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis. Br J Pharmacol. 2018; 175: 2689-708.

[131] Wei MG, Sun W, He WM, Ni L, Yang YY. Ferulic acid attenuates TGF-β1-induced renal cellular fibrosis in NRK-52E cells by inhibiting Smad/ILK/snail pathway. Evid Based Complement Alternat Med. 2015; 2015: 1-7.

[132] Li Y, Hu Q, Li C, Liang K, Xiang Y, Hsiao H, et al. PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease. J Clin Invest. 2019; 129: 1129-51.

[133] Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, et al. EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int. 2005; 67: 867-74.

[134] Zhiqiang W, Juan C, Xu Z, Di Y, Deyu X, Guoyuan L. EPA attenuates epithelial-mesenchymal transition and fibrosis through the TGF-β1/Smad3/ILK pathway in renal tubular epithelial HK-2 cells by up-regulating miR-541. Int J Clin Exp Pathol. 2019; 12: 2516-25.

[135] Lyu X, Hu M, Peng J, Zhang X, Sanders YY. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Ther Adv Chronic Dis. 2019; 10: 204062231986269.

[136] Choi SY, Kee HJ, Kurz T, Hansen FK, Ryu Y, Kim GR, et al. Class I HDACs specifically regulate E-cadherin expression in human renal epithelial cells. J Cell Mol Med. 2016; 20: 2289-98.

[137] Rossi L, Battistelli C, de Turris V, Noce V, Zwergel C, Valente S, et al. HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal. Sci Rep. 2018; 8: 8492.

[138] Choi SY, Ryu Y, Kee HJ, Cho SN, Kim GR, Cho JY, et al. Tubastatin a suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes. Vasc Pharmacol. 2015; 72: 130-40.

[139] Saito S, Zhuang Y, Shan B, Danchuk S, Luo F, Korfei M, et al. Tubastatin ameliorates pulmonary fibrosis by targeting the TGFbeta-PI3K-Akt pathway. PLoS One. 2017; 12: e0186615.

[140] Chen L, Alam A, Pac-Soo A, Chen Q, Shang Y, Zhao H, et al. Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo. Lab Investig. 2021; 101: 1166-75.

[141] Nguyen-Thanh T, Kim D, Lee S, Kim W, Park SK, Kang KP. Inhibition of histone deacetylase 1 ameliorates renal tubulointerstitial fibrosis via modulation of inflammation and extracellular matrix gene transcription in mice. Int J Mol Med. 2018; 41: 95-106.

[142] Zhang Y, Zou J, Tolbert E, Zhao TC, Bayliss G, Zhuang S. Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis. FASEB J. 2020; 34: 7295-310.

[143] Tseng WC, Tsai MT, Chen NJ, Tarng DC. Trichostatin a alleviates renal interstitial fibrosis through modulation of the M2 macrophage subpopulation. Int J Mol Sci. 2020; 21, 5966.

[144] Tung CW, Hsu YC, Cai CJ, Shih YH, Wang CJ, Chang PJ, et al. Trichostatin a ameliorates renal tubulointerstitial fibrosis through modulation of the JNK-dependent Notch-2 signaling pathway. Sci Rep. 2017; 7: 14495.

[145] Williams VR, Konvalinka A, Song X, Zhou X, John R, Pei Y, et al. Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets. Kidney Int. 2020; 98: 116-32.

[146] Ozel M, Baskol M, Akalin H, Baskol G. Suberoylanilide Hydroxamic acid (SAHA) reduces fibrosis markers and deactivates human stellate cells via the epithelial-mesenchymal transition (EMT). Cell Biochem Biophys. 2021; 79: 349-57.

[147] Zhang YQ, Liu YJ, Mao YF, Dong WW, Zhu XY, Jiang L. Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-beta1 signaling. Clin Nutr. 2015; 34: 752-60.

[148] Choi SY, Piao ZH, Jin L, Kim JH, Kim GR, Ryu Y, et al. Piceatannol attenuates renal fibrosis induced by unilateral ureteral obstruction via downregulation of histone deacetylase 4/5 or p38-MAPK Signaling. PLoS One. 2016; 11: e0167340.

[149] Xiong C, Guan Y, Zhou X, Liu L, Zhuang MA, Zhang W, et al. Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis. FASEB J. 2019; 33: 8249-62.

[150] Morigi M, Perico L, Benigni A. Sirtuins in renal health and disease. J Am Soc Nephrol. 2018; 29: 1799-809.

[151] Liu S, Zhao M, Zhou Y, Wang C, Yuan Y, Li L, et al. Resveratrol exerts dose-dependent anti-fibrotic or pro-fibrotic effects in kidneys: a potential risk to individuals with impaired kidney function. Phytomedicine. 2019; 57: 223-35.

[152] He Y, Lu R, Wu J, Pang Y, Li J, Chen J, et al. Salvianolic acid B attenuates epithelial-mesenchymal transition in renal fibrosis rats through activating Sirt1-mediated autophagy. Biomed Pharmacother. 2020; 128: 110241.

[153] Quan Y, Park W, Jin J, Kim W, Park SK, Kang KP. Sirtuin 3 activation by Honokiol decreases unilateral ureteral obstruction-induced renal inflammation and fibrosis via regulation of mitochondrial dynamics and the renal NF-κB-TGF-β1/Smad Signaling pathway. Int J Mol Sci. 2020; 21: 402.

[154] Cai J, Liu Z, Huang X, Shu S, Hu X, Zheng M, et al. The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression. Kidney Int. 2020; 97: 106-18.

[155] Meng Q, Zhai X, Yuan Y, Ji Q, Zhang P. lncRNA ZEB1-AS1 inhibits high glucose-induced EMT and fibrogenesis by regulating the miR-216a-5p/BMP7 axis in diabetic nephropathy. Braz J Med Biol Res. 2020; 53: e9288.

[156] Yu F, Lu Z, Chen B, Wu X, Dong P, Zheng J. Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated Patched1 methylation. J Cell Mol Med. 2015; 19: 2617-32.

[157] Bai S, Xiong X, Tang B, Ji T, Li X, Qu X, et al. Hsa-miR-199b-3p prevents the epithelial-mesenchymal transition and dysfunction of the renal tubule by regulating E-cadherin through targeting KDM6A in diabetic nephropathy. Oxidative Med Cell Longev. 2021; 2021: 1-17.

[158] Kim S, Jeong CH, Song SH, Um JE, Kim HS, Yun JS, et al. Micellized protein transduction domain-bone morphogenetic Protein-7 efficiently blocks renal fibrosis via inhibition of transforming growth factor-Beta-mediated epithelial-mesenchymal transition. Front Pharmacol. 2020; 11: 591275.

[159] Meng XM, Chung AC, Lan HY. Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond). 2013; 124: 243-54.

[160] Song Y, Lv S, Wang F, Liu X, Cheng J, Liu S, et al. Overexpression of BMP-7 reverses TGF-β1-induced epithelial-mesenchymal transition by attenuating the Wnt3/β-catenin and TGF-β1/Smad2/3 signaling pathways in HK-2 cells. Mol Med Rep. 2020; 21: 833-41.

[161] Wang Y, Liang D, Zhu Z, Li X, An G, Niu P, et al. Bone morphogenetic protein-7 prevented epithelial-mesenchymal transition in RLE-6TN cells. Toxicol Res (Camb). 2016; 5: 931-7.

[162] Liu L, Wang Y, Yan R, Liang L, Zhou X, Liu H, et al. BMP-7 inhibits renal fibrosis in diabetic nephropathy via miR-21 downregulation. Life Sci. 2019; 238: 116957.

[163] Ling H, Roux E, Hempel D, Tao J, Smith M, Lonning S, et al. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in Thioacetamide-treated rats. PLoS One. 2013; 8: e54499.

[164] Yamagami Y, Kawami M, Ojima T, Futatsugi S, Yumoto R, Takano M. Role of plasminogen activator inhibitor-1 in methotrexate-induced epithelial-mesenchymal transition in alveolar epithelial A549 cells. Biochem Biophys Res Commun. 2020; 525: 543-8.

[165] McGaraughty S, Davis-Taber RA, Zhu CZ, Cole TB, Nikkel AL, Chhaya M, et al. Targeting anti-TGF-beta therapy to fibrotic kidneys with a dual specificity antibody approach. J Am Soc Nephrol. 2017; 28: 3616-26.

[166] Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014; 32: 51-82.

[167] Song Y, Peng C, Lv S, Cheng J, Liu S, Wen Q, et al. Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway. Int Immunopharmacol. 2017; 44: 115-22.

[168] Yu Y, Hu D, Zhou Y, Xiang H, Liu B, Shen L, et al. Human umbilical cord mesenchymal stem cell attenuates renal fibrosis via TGF-β/Smad signaling pathways in vivo and in vitro. Eur J Pharmacol. 2020; 883: 173343.

[169] Jin J, Qian F, Zheng D, He W, Gong J, He Q. Mesenchymal stem cells attenuate renal fibrosis via exosomes-mediated delivery of microRNA let-7i-5p Antagomir. Int J Nanomedicine. 2021; 16: 3565-78.

[170] Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002; 4: 648-57.

[171] Lee M, Kim SH, Jhee JH, Kim TY, Choi HY, Kim HJ, et al. Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis. Stem Cell Res Ther. 2020; 11: 422.

[172] Shi Z, Wang Q, Zhang Y, Jiang D. Extracellular vesicles produced by bone marrow mesenchymal stem cells attenuate renal fibrosis, in part by inhibiting the RhoA/ROCK pathway, in a UUO rat model. Stem Cell Res Ther. 2020; 11: 253.

[173] Zhang F, Wan X, Cao YZ, Sun D, Cao CC. Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β-catenin pathway in kidneys after acute injury. Cell Biol Int. 2018; 42: 1670-9.

[174] Nathan SD, Albera C, Bradford WZ, Costabel U, Glaspole I, Glassberg MK, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med. 2017; 5: 33-41.

[175] Galli JA, Pandya A, Vega-Olivo M, Dass C, Zhao H, Criner GJ. Pirfenidone and nintedanib for pulmonary fibrosis in clinical practice: tolerability and adverse drug reactions. Respirology. 2017; 22: 1171-8.

[176] Yao Y, Li Y, Zeng X, Ye Z, Li X, Zhang L. Losartan alleviates renal fibrosis and inhibits endothelial-to-mesenchymal transition (EMT) under high-fat diet-induced Hyperglycemia. Front Pharmacol. 2018; 9: 1213.

[177] Bartko PE, Dal-Bianco JP, Guerrero JL, Beaudoin J, Szymanski C, Kim DH, et al. Effect of losartan on mitral valve changes after myocardial infarction. J Am Coll Cardiol. 2017; 70: 1232-44.

[178] Arnoni CP, Maquigussa E, Passos CS, Pereira LG, Boim MA. Inhibition of cellular transdifferentiation by losartan minimizes but does not reverse type 2 diabetes-induced renal fibrosis. J Renin-Angiotensin-Aldosterone Syst. 2015; 16: 469-80.

[179] Wu T, Chen JM, Xiao TG, Shu XB, Xu HC, Yang LL, et al. Qinggan Huoxue recipe suppresses epithelial-to-mesenchymal transition in alcoholic liver fibrosis through TGF-β1/Smad signaling pathway. World J Gastroenterol. 2016; 22: 4695-706.

[180] Meng L, Zhang X, Wang H, Dong H, Gu X, Yu X, et al. Yangyin Yiqi mixture ameliorates bleomycin-induced pulmonary fibrosis in rats through inhibiting TGF-β1/Smad pathway and epithelial to mesenchymal transition. Evid Based Complement Alternat Med. 2019; 2019: 1-13.

[181] Yin ZF, Wei YL, Wang X, Wang LN, Li X. Buyang Huanwu Tang inhibits cellular epithelial-to-mesenchymal transition by inhibiting TGF-β1 activation of PI3K/Akt signaling pathway in pulmonary fibrosis model in vitro. BMC Complement Med Ther. 2020; 20: 13.