CoChat
Sign Up
Cited by 41TGF-β signaling in diseasesHippo pathway signaling and YAP/TAZLiver physiology and pathology

Profibrotic epithelial phenotype: a central role for MRTF and TAZ

Open access
Bialik, Janne Folke, Ding, Mei, Speight, Pam, Dan, Qinghong, Miranda, Maria Zena, Di Ciano-Oliveira, Caterina, Kofler, Michael M., Rotstein, Ori D. +3 more·2019·Scientific Reports
DOI 10.1038/s41598-019-40764-7PMC PMC6416270
Open this paper in CoChat — free accountOpen PDF

Abstract

Epithelial injury is a key initiator of fibrosis but - in contrast to the previous paradigm - the epithelium in situ does not undergo wide-spread epithelial-mesenchymal/myofibroblast transition (EMT/EMyT). Instead, it assumes a Profibrotic Epithelial Phenotype (PEP) characterized by fibrogenic cytokine production. The transcriptional mechanisms underlying PEP are undefined. As we have shown that two RhoA/cytoskeleton-regulated transcriptional coactivators, Myocardin-related transcription factor (MRTF) and TAZ, are indispensable for EMyT, we asked if they might mediate PEP as well. Here we show that mechanical stress (cyclic stretch) increased the expression of transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), platelet-derived growth factor and Indian Hedgehog mRNA in LLC-PK1 tubular cells. These responses were mitigated by siRNA-mediated silencing or pharmacological inhibition of MRTF (CCG-1423) or TAZ (verteporfin). RhoA inhibition exerted similar effects. Unilateral ureteral obstruction, a murine model of mechanically-triggered kidney fibrosis, induced tubular RhoA activation along with overexpression/nuclear accumulation of MRTF and TAZ, and increased transcription of the above-mentioned cytokines. Laser capture microdissection revealed TAZ, TGFβ1 and CTGF induction specifically in the tubular epithelium. CCG-1423 suppressed total renal and tubular expression of these proteins. Thus, MRTF regulates epithelial TAZ expression, and both MRTF and TAZ are critical mediators of PEP-related epithelial cytokine production.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-019-40764-7

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 89

  1. [1]Duffield JS Cellular and molecular mechanisms in kidney fibrosis The Journal of clinical investigation 2014 124 2299 2306 24892703 PMC4038570
  2. [2]Iwano M Neilson EG Mechanisms of tubulointerstitial fibrosis Curr Opin Nephrol Hypertens 2004 13 279 284 15073485
  3. [3]Nangaku M Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure J Am Soc Nephrol 2006 17 17 25 16291837
  4. [4]Liu Y Renal fibrosis: new insights into the pathogenesis and therapeutics Kidney Int 2006 69 213 217 16408108
  5. [5]Humphreys BD Mechanisms of Renal Fibrosis Annu Rev Physiol 2018 80 309 326 29068765
  6. [6]Tang WW Van GY Qi M Myofibroblast and alpha 1 (III) collagen expression in experimental tubulointerstitial nephritis Kidney Int 1997 51 926 931 9067932
  7. [7]Hinz B The myofibroblast: one function, multiple origins Am J Pathol 2007 170 1807 1816 17525249 PMC1899462
  8. [8]Falke LL Gholizadeh S Goldschmeding R Kok RJ Nguyen TQ Diverse origins of the myofibroblast-implications for kidney fibrosis Nat Rev Nephrol 2015 11 233 244 25584804
  9. [9]Louis K Hertig A How tubular epithelial cells dictate the rate of renal fibrogenesis? World J Nephrol 2015 4 367 373 26167460 PMC4491927
  10. [10]Tan RJ Zhou D Liu Y Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury Kidney Dis (Basel) 2016 2 136 144 27921041 PMC5123005
  11. [11]Schnaper HW The Tubulointerstitial Pathophysiology of Progressive Kidney Disease Adv Chronic Kidney Dis 2017 24 107 116 28284376 PMC5351778
  12. [12]Yang L Besschetnova TY Brooks CR Shah JV Bonventre JV Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury Nature medicine 2010 16 535 543 20436483 PMC3928013
  13. [13]Grgic I Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis Kidney Int 2012 82 172 183 22437410 PMC3480325
  14. [14]Zeisberg M Kalluri R The role of epithelial-to-mesenchymal transition in renal fibrosis J Mol Med 2004 82 175 181 14752606
  15. [15]Zeisberg M Duffield JS Resolved: EMT produces fibroblasts in the kidney J Am Soc Nephrol 2010 21 1247 1253 20651165
  16. [16]Quaggin SE Kapus A Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition Kidney Int 2011 80 41 50 21430641
  17. [17]Fan JM Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro Kidney Int 1999 56 1455 1467 10504497
  18. [18]Masszi A Central role for Rho in TGF-beta1-induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition Am J Physiol Renal Physiol 2003 284 F911 924 12505862
  19. [19]Iwano M Evidence that fibroblasts derive from epithelium during tissue fibrosis The Journal of clinical investigation 2002 110 341 350 12163453 PMC151091
  20. [20]Humphreys BD Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis Am J Pathol 2010 176 85 97 20008127 PMC2797872
  21. [21]Duffield JS Humphreys BD Origin of new cells in the adult kidney: results from genetic labeling techniques Kidney Int 2011 79 494 501 20861816
  22. [22]Grgic I Duffield JS Humphreys BD The origin of interstitial myofibroblasts in chronic kidney disease Pediatr Nephrol 2012 27 183 193 21311912 PMC3116994
  23. [23]LeBleu VS Origin and function of myofibroblasts in kidney fibrosis Nature medicine 2013 19 1047 1053 23817022 PMC4067127
  24. [24]Grande MT Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease Nature medicine 2015 21 989 997 26236989
  25. [25]Lovisa, S. et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nature medicine21 (2015). PMC4587560 26236991
  26. [26]Wu CF Transforming growth factor beta-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis Am J Pathol 2013 182 118 131 23142380 PMC3538028
  27. [27]Chen YT Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis Kidney Int 2011 80 1170 1181 21716259
  28. [28]Fabian SL Hedgehog-Gli pathway activation during kidney fibrosis Am J Pathol 2012 180 1441 1453 22342522 PMC3349903
  29. [29]Fukuda K Yoshitomi K Yanagida T Tokumoto M Hirakata H Quantification of TGF-beta1 mRNA along rat nephron in obstructive nephropathy Am J Physiol Renal Physiol 2001 281 F513 521 11502600
  30. [30]Masszi A Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin Am J Pathol 2004 165 1955 1967 15579439 PMC1618715
  31. [31]Fan L Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathway Mol Biol Cell 2007 18 1083 1097 17215519 PMC1805104
  32. [32]Masszi A Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3 J Cell Biol 2010 188 383 399 20123992 PMC2819691
  33. [34]Speight P Nakano H Kelley TJ Hinz B Kapus A Differential topical susceptibility to TGFbeta in intact and injured regions of the epithelium: key role in myofibroblast transition Mol Biol Cell 2013 24 3326 3336 24006486 PMC3814143
  34. [35]Speight P Kofler M Szaszi K Kapus A Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFbeta-regulated Smad3 Nat Commun 2016 7 11642 27189435 PMC4873981
  35. [36]Finch-Edmondson M Sudol M Framework to function: mechanosensitive regulators of gene transcription Cell Mol Biol Lett 2016 21 28 28536630 PMC5415767
  36. [37]Panciera T Azzolin L Cordenonsi M Piccolo S Mechanobiology of YAP and TAZ in physiology and disease Nat Rev Mol Cell Biol, Nat Rev Mol Cell Biol 2017 18 758 770 28951564 PMC6192510
  37. [38]Miralles F Posern G Zaromytidou AI Treisman R Actin dynamics control SRF activity by regulation of its coactivator MAL Cell 2003 113 329 342 12732141
  38. [39]Olson EN Nordheim A Linking actin dynamics and gene transcription to drive cellular motile functions Nat Rev Mol Cell Biol 2010 11 353 365 20414257 PMC3073350
  39. [40]Busche S Descot A Julien S Genth H Posern G Epithelial cell-cell contacts regulate SRF-mediated transcription via Rac-actin-MAL signalling J Cell Sci 2008 121 1025 1035 18334560
  40. [41]Dupont S Role of YAP/TAZ in mechanotransduction Nature 2011 474 179 183 21654799
  41. [42]Varelas X The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway Developmental cell 2010 19 831 844 21145499
  42. [43]Sun Q Defining the mammalian CArGome Genome Res 2006 16 197 207 16365378 PMC1361715
  43. [44]Meng Z Moroishi T Guan KL Mechanisms of Hippo pathway regulation Genes Dev 2016 30 1 17 26728553 PMC4701972
  44. [45]Lin KC Park HW Guan KL Regulation of the Hippo Pathway Transcription Factor TEAD Trends Biochem Sci 2017 42 862 872 28964625 PMC5735856
  45. [46]Morita T Mayanagi T Sobue K Dual roles of myocardin-related transcription factors in epithelial mesenchymal transition via slug induction and actin remodeling J Cell Biol 2007 179 1027 1042 18056415 PMC2099179
  46. [47]Varelas X TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal Nature cell biology 2008 10 837 848 18568018
  47. [48]Miranda MZ TGF-beta1 regulates the expression and transcriptional activity of TAZ protein via a Smad3-independent, myocardin-related transcription factor-mediated mechanism J Biol Chem 2017 292 14902 14920 28739802 PMC5592669
  48. [49]Small EM Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction Circulation research 2010 107 294 304 20558820 PMC2921870
  49. [50]Xu H Myocardin-Related Transcription Factor A Epigenetically Regulates Renal Fibrosis in Diabetic Nephropathy J Am Soc Nephrol 2015 26 1648 1660 25349198 PMC4483593
  50. [51]Liu F Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis American journal of physiology. Lung cellular and molecular physiology 2015 308 L344 357 25502501 PMC4329470
  51. [52]Bertero T A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions Sci Rep 2015 5 18277 26667495 PMC4678880
  52. [53]Szeto SG YAP/TAZ Are Mechanoregulators of TGF-beta-Smad Signaling and Renal Fibrogenesis J Am Soc Nephrol 2016 27 3117 3128 26961347 PMC5042658
  53. [54]Grabias BM Konstantopoulos K The physical basis of renal fibrosis: effects of altered hydrodynamic forces on kidney homeostasis Am J Physiol Renal Physiol 2014 306 F473 485 24352503
  54. [55]Chevalier RL Thornhill BA Forbes MS Kiley SC Mechanisms of renal injury and progression of renal disease in congenital obstructive nephropathy Pediatr Nephrol 2010 25 687 697 19844747
  55. [56]Rohatgi R Flores D Intratubular hydrodynamic forces influence tubulointerstitial fibrosis in the kidney Curr Opin Nephrol Hypertens 2010 19 65 71 19851105 PMC2887746
  56. [57]Weinbaum S Duan Y Satlin LM Wang T Weinstein AM Mechanotransduction in the renal tubule Am J Physiol Renal Physiol 2010 299 F1220 1236 20810611 PMC3006307
  57. [58]Rozycki M Myocardin-related Transcription Factor Regulates Nox4 Protein Expression: LINKING CYTOSKELETAL ORGANIZATION TO REDOX STATE J Biol Chem 2016 291 227 243 26555261 PMC4697158
  58. [59]Hayashi K Watanabe B Nakagawa Y Minami S Morita T RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling PloS one 2014 9 e89016 24558465 PMC3928398
  59. [60]Watanabe B Stereospecific Inhibitory Effects of CCG-1423 on the Cellular Events Mediated by Myocardin-Related Transcription Factor A PloS one 2015 10 e0136242 26295164 PMC4546662
  60. [61]Liu-Chittenden Y Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP Genes Dev 2012 26 1300 1305 22677547 PMC3387657
  61. [62]Gibault F Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway ChemMedChem 2017 12 954 961 28334506
  62. [63]Shang X Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases Chem Biol 2012 19 699 710 22726684 PMC3383629
  63. [64]Klahr S Morrissey J Obstructive nephropathy and renal fibrosis Am J Physiol Renal Physiol 2002 283 F861 875 12372761
  64. [65]Sandbo N Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-beta American journal of physiology. Lung cellular and molecular physiology 2011 301 L656 666 21856814 PMC3213993
  65. [66]Scharenberg MA TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms J Cell Sci 2014 127 1079 1091 24424023
  66. [67]Hinson JS Medlin MD Taylor JM Mack CP Regulation of myocardin factor protein stability by the LIM-only protein FHL2 Am J Physiol Heart Circ Physiol 2008 295 H1067 H1075 18586895 PMC2544497
  67. [68]Tian W Myocardin-related transcription factor A (MRTF-A) plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-beta signaling Int J Biochem Cell Biol 2016 71 35 43 26693892
  68. [69]Sisson TH Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis Am J Pathol 2015 185 969 986 25681733 PMC4380846
  69. [70]Shiwen X A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis PloS one 2015 10 e0126015 25955164 PMC4425676
  70. [71]Haak AJ Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury The Journal of pharmacology and experimental therapeutics 2014 349 480 486 24706986 PMC4019321
  71. [72]Sakai N LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation FASEB J 2013 27 1830 1846 23322166 PMC3633809
  72. [73]Hutchings KM Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma Bioorg Med Chem Lett 2017 27 1744 1749 28285914 PMC5395305
  73. [74]Chen J Harris RC Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney J Am Soc Nephrol 2016 27 1689 1700 26453611 PMC4884112
  74. [75]Rinschen MM YAP-mediated mechanotransduction determines the podocyte’s response to damage Sci Signal 2017 10 474 28400537
  75. [76]Martin K PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis Nat Commun 2016 7 12502 27535340 PMC4992158
  76. [77]Esnault C Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts Genes Dev 2014 28 943 958 24732378 PMC4018493
  77. [78]Zhao B TEAD mediates YAP-dependent gene induction and growth control Genes Dev 2008 22 1962 1971 18579750 PMC2492741
  78. [79]Hamzeh MT Sridhara R Alexander LD Cyclic stretch-induced TGF-beta1 and fibronectin expression is mediated by beta1-integrin through c-Src- and STAT3-dependent pathways in renal epithelial cells Am J Physiol Renal Physiol 2015 308 F425 436 25477471 PMC4422350
  79. [80]Seo E The Hippo-Salvador signaling pathway regulates renal tubulointerstitial fibrosis Sci Rep 2016 6 31931 27550469 PMC4994041
  80. [81]Wu Q Zhang Y Chen Q Indian hedgehog is an essential component of mechanotransduction complex to stimulate chondrocyte proliferation J Biol Chem 2001 276 35290 35296 11466306
  81. [82]Wang X Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis Cell Metab 2016 24 848 862 28068223 PMC5226184
  82. [83]Anorga S Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype FASEB J 2018 32 2644 2657 29298862 PMC5901380
  83. [84]Liang M Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis J Am Soc Nephrol 2017 28 3278 3290 28768710 PMC5661271
  84. [85]Lee M San Martin A Valdivia A Martin-Garrido A Griendling KK Redox-Sensitive Regulation of Myocardin-Related Transcription Factor (MRTF-A) Phosphorylation via Palladin in Vascular Smooth Muscle Cell Differentiation Marker Gene Expression PloS one 2016 11 e0153199 27088725 PMC4835087
  85. [86]Noguchi S TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts Sci Rep 2017 7 42595 28195168 PMC5307361
  86. [88]Liu L Myocardin-related transcription factor A (MRTF-A) contributes to acute kidney injury by regulating macrophage ROS production Biochim Biophys Acta 2018 1864 3109 3121 29908908
  87. [89]Ly DL Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton Am J Physiol Cell Physiol 2013 304 C115 127 23054059 PMC3546806
  88. [90]Evelyn CR CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling Mol Cancer Ther 2007 6 2249 2260 17699722
  89. [91]Schindelin J Fiji: an open-source platform for biological-image analysis Nat Methods 2012 9 676 682 22743772 PMC3855844

Cited by

Sorted by citations

Authors
Bialik, J. F., Ding, M., Speight, P., Dan, Q., Miranda, M. Z., Di Ciano-Oliveira, C., Kofler, M. M., Rotstein, O. D., Pedersen, S. F., Szászi, K., & Kapus, A.
Affiliations
  • University of Copenhagen (DK)
  • St. Michael's Hospital (CA)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-03-13
Volume
9
Issue
1
Pages
4323-4323
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-40764-7
PMC
PMC6416270
OpenAlex
W2920935501
Cited by
41
References
2
Citations by year
2026: 4 · 2025: 2 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 8
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Kidney Foundation of Canada
  • Gouvernement du Canada | Canadian Institutes of Health Research (MOP-130463, MOP-142409)
  • Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (RGPIN227-908-13)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
MRTF, TAZ, RhoA, epithelial-mesenchymal transition, myofibroblast differentiation, renal fibrosis, mechanical stretch, TGF-β1, connective tissue growth factor, platelet-derived growth factor, Indian hedgehog, unilateral ureteral obstruction, tubular epithelium, transcriptional coactivator, CCG-1423, verteporfin
MeSH terms
Animals, Epithelial Cells, Fibrosis, Kidney, Stress, Mechanical, Transcription Factors, Trans-Activators, Cytokines, rhoA GTP-Binding Protein, Adaptor Proteins, Signal Transducing, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review