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The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology

  • Wendy C. Burns (a1) and Merlin C. Thomas (a1)

Common to all forms of chronic kidney disease is the progressive scarring of the tubulo-interstitial space, associated with the acquisition and accumulation of activated myofibroblasts. Many of these myofibroblasts are generated when tubular epithelial cells progressively lose their epithelial characteristics (cell–cell contact, microvilli, tight-junction proteins, apical–basal polarity) and acquire features of a mesenchymal lineage, including stress fibres, filopodia and augmented matrix synthesis. This process, known as epithelial to mesenchymal transition (EMT), plays an important role in progressive kidney disease. For EMT to occur in tubular cells, the transcriptional activation (and derepression) of genes required to sustain mesenchymal-type structures and functions (e.g. vimentin, α-smooth muscle actin) must occur alongside repression (or deactivation) of genes that act to maintain the epithelial phenotype (e.g. E-cadherin, bone morphogenic protein 7). Several factors have been suggested as potential initiators of EMT. With a few key exceptions, these triggers require the induction of transforming growth factor β (TGF-β) and downstream mediators, including SMADs, CTGF, ILK and SNAI1. Activation of TGF-β receptors is also able to stimulate a range of additional pathways (so-called non-SMAD activation), including RhoA, mitogen-activated protein kinase and phosphoinositide 3-kinase signalling cascades, that also contribute to EMT and renal fibrogenesis. This review examines in detail the molecular mediators of EMT in tubular cells and its potential role as a long-lasting mediator of metabolic stress.

Corresponding author
*Corresponding author: Merlin C. Thomas, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, Melbourne, VIC 8008, Australia. E-mail:
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1J. Yang and Y. Liu (2001) Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. American Journal of Pathology 159, 1465-1475

2Y. Liu (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. Journal of the American Society of Nephrology 15, 1-12

4M. Iwano (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. Journal of Clinical Investigation 110, 341-350

5M.D. Oldfield (2001) Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). Journal of Clinical Investigation 108, 1853-1863

6R. Kalluri and E.G. Neilson (2003) Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation 112, 1776-1784

7M.P. Rastaldi (2002) Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney International 62, 137-146

8M. Zeisberg and E.G. Neilson (2009) Biomarkers for epithelial-mesenchymal transitions. Journal of Clinical Investigation 119, 1429-1437

9E.D. Hay and A. Zuk (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. American Journal of Kidney Diseases 26, 678-690

10H. Acloque (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. Journal of Clinical Investigation 119, 1438-1449

12W. Qi (2005) Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis. American Journal of Physiology – Renal Physiology 288, F800-809

13P.J. Margetts (2005) Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. Journal of the American Society of Nephrology 16, 425-436

15J.M. Fan (2001) Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. American Journal of Kidney Diseases 37, 820-831

16F. Strutz (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney International 61, 1714-1728

17H. Ha and H.B. Lee (2003) Reactive oxygen species and matrix remodeling in diabetic kidney. Journal of the American Society of Nephrology 14, S246-249

18H.Y. Lan (2003) Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Current Opinion in Nephrology and Hypertension 12, 25-29

19J.M. Lee (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. Journal of Cell Biology 172, 973-981

20J. Zavadil and E.P. Bottinger (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24, 5764-5774

22M. Zeisberg (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. American Journal of Pathology 159, 1313-1321

23J. Massague and D. Wotton (2000) Transcriptional control by the TGF-beta/Smad signaling system. EMBO Journal 19, 1745-1754

24E.P. Bottinger and M. Bitzer (2002) TGF-beta signaling in renal disease. Journal of the American Society of Nephrology 13, 2600-2610

25J.M. Fan (1999) Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney International 56, 1455-1467

26J.L. Wrana (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71, 1003-1014

27Q.L. Wang (2010) Fuzheng Huayu recipe and vitamin E reverse renal interstitial fibrosis through counteracting TGF-beta1-induced epithelial-to-mesenchymal transition. Journal of Ethnopharmacology 127, 631-640

28M. Petersen (2008) Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney International 73, 705-715

29H.W. Schnaper (2003) TGF-beta signal transduction and mesangial cell fibrogenesis. American Journal of Physiology – Renal Physiology 284, F243-252

30M.K. Phanish (2006) The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1 responses in human proximal-tubule epithelial cells. Biochemical Journal 393, 601-607

31J. Zavadil (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO Journal 23, 1155-1165

32M. Sato (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. Journal of Clinical Investigation 112, 1486-1494

34P. ten Dijke , K. Miyazono and C.H. Heldin (2000) Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends in Biochemical Sciences 25, 64-70

35F. Itoh (2001) Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO Journal 20, 4132-4142

36A.C. Chung (2009) Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice. Nephrology Dialysis Transplantation 24, 1443-1454

37H.Y. Lan (2003) Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. Journal of the American Society of Nephrology 14, 1535-1548

38Y. Li (2003) Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. Journal of Clinical Investigation 112, 503-516

39J.H. Li (2002) Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation. Journal of the American Society of Nephrology 13, 1464-1472

40G. Carvajal (2008) Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation. Kidney International 74, 585-595

41H. Fukasawa (2004) Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proceedings of the National Academy of Sciences of the United States of America 101, 8687-8692

42M. Schiffer (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. Journal of Clinical Investigation 108, 807-816

43J. Massague (2000) How cells read TGF-beta signals. Nature Reviews Molecular Cell Biology 1, 169-178

44Y. Goto (2004) Augmented cytoplasmic Smad4 induces acceleration of TGF-beta1 signaling in renal tubulointerstitial cells of hereditary nephrotic ICGN mice with chronic renal fibrosis; possible role for myofibroblastic differentiation. Cell and Tissue Research 315, 209-221

45B.S. Oemar and T.F. Luscher (1997) Connective tissue growth factor. Friend or foe? Arteriosclerosis Thrombosis and Vascular Biology 17, 1483-1489

46G.R. Grotendorst (1997) Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine and Growth Factor Reviews 8, 171-179

47W.C. Burns , P. Kantharidis and M.C. Thomas (2007) The role of tubular epithelial-mesenchymal transition in progressive kidney disease. Cells Tissues Organs 185, 222-231

48W.C. Burns (2006) Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. Journal of the American Society of Nephrology 17, 2484-2494

49H. Peinado , M. Quintanilla and A. Cano (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. Journal of Biological Chemistry 278, 21113-21123

50H. Okada (2005) Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. Journal of the American Society of Nephrology 16, 133-143

51L. Chen (2006) Influence of connective tissue growth factor antisense oligonucleotide on angiotensin II-induced epithelial mesenchymal transition in HK2 cells. Acta Pharmacologica Sinica 27, 1029-1036

52T. Mori (1999) Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. Journal of Cellular Physiology 181, 153-159

53H. Yokoi (2004) Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. Journal of the American Society of Nephrology 15, 1430-1440

54F.A. van Nieuwenhoven (2005) Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrology Dialysis Transplantation 20, 6-10

55N. Abdel Wahab and R.M. Mason (2004) Connective tissue growth factor and renal diseases: some answers, more questions. Current Opinion in Nephrology and Hypertension 13, 53-58

56N.A. Wahab , B.S. Weston and R.M. Mason (2005) Modulation of the TGFbeta/Smad signaling pathway in mesangial cells by CTGF/CCN2. Experimental Cell Research 307, 305-314

57N.A. Wahab , B.S. Weston and R.M. Mason (2005) Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA. Journal of the American Society of Nephrology 16, 340-351

58X.C. Liu (2007) Role of ERK1/2 and PI3-K in the regulation of CTGF-induced ILK expression in HK-2 cells. Clinica Chimica Acta 382, 89-94

59T. Nishida (1998) Demonstration of receptors specific for connective tissue growth factor on a human chondrocytic cell line (HCS-2/8). Biochemical and Biophysical Research Communications 247, 905-909

60P.R. Segarini (2001) The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. Journal of Biological Chemistry 276, 40659-40667

61Y. Chen (2001) Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome. Experimental Cell Research 271, 109-117

62B.C. Liu (2008) Inhibition of integrin-linked kinase via a siRNA expression plasmid attenuates connective tissue growth factor-induced human proximal tubular epithelial cells to mesenchymal transition. American Journal of Nephrology 28, 143-151

63J.P. Thiery (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890

64J. Ikenouchi (2003) Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. Journal of Cell Science 116, 1959-1967

65S. Thuault (2008) HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. Journal of Biological Chemistry 283, 33437-33446

66S. Thuault (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. Journal of Cell Biology 174, 175-183

67T. Vincent (2009) A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nature Cell Biology 11, 943-950

69M. Jorda (2005) Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. Journal of Cell Science 118, 3371-3385

70R. Derynck and Y.E. Zhang (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425, 577-584

71T. Kokudo (2008) Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. Journal of Cell Science 121, 3317-3324

72Y.E. Zhang (2009) Non-Smad pathways in TGF-beta signaling. Cell Research 19, 128-139

73V. Bolos (2003) The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. Journal of Cell Science 116, 499-511

74N.A. Bhowmick (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Molecular Biology of the Cell 12, 27-36

75E. Kolosionek (2009) Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4. Molecular Biology of the Cell 20, 4751-4765

76N.A. Bhowmick (2003) TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proceedings of the National Academy of Sciences of the United States of America 100, 15548-15553

77R. Rodrigues-Diez (2008) Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharmaceutical Research 25, 2447-2461

78S. Patel (2005) RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation. Journal of the American Society of Nephrology 16, 1977-1984

79D.Y. Rhyu (2005) Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. Journal of the American Society of Nephrology 16, 667-675

80A.V. Bakin (2000) Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. Journal of Biological Chemistry 275, 36803-36810

81Q. Zhu (2007) Dual role of SnoN in mammalian tumorigenesis. Molecular and Cellular Biology 27, 324-339

82N.G. Docherty (2006) TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. American Journal of Physiology – Renal Physiology 290, F1202-1212

83C.E. Winbanks (2007) Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation. International Journal of Biochemistry and Cell Biology 39, 206-219

84J. Morrissey (2002) Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease. Journal of the American Society of Nephrology 13, 1499-1508

85D.W. Walsh (2008) Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochimica et Biophysica Acta 1782, 10-21

86M. Yoshikawa (2007) Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. Journal of the American Society of Nephrology 18, 58-65

87J. Deheuninck and K. Luo (2009) Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Research 19, 47-57

88K. Miyazono , H. Suzuki and T. Imamura (2003) Regulation of TGF-beta signaling and its roles in progression of tumors. Cancer Science 94, 230-234

89J. Zavadil (2007) Transforming growth factor-beta and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 185, 157-161

90M. Kato (2007) MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proceedings of the National Academy of Sciences of the United States of America 104, 3432-3437

91S.S. Huang and J.S. Huang (2005) TGF-beta control of cell proliferation. Journal of Cellular Biochemistry 96, 447-462

92K. Hu (2008) tPA protects renal interstitial fibroblasts and myofibroblasts from apoptosis. Journal of the American Society of Nephrology 19, 503-514

94A.E. Postlethwaite , H. Shigemitsu and S. Kanangat (2004) Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis. Current Opinion in Rheumatology 16, 733-738

95M. Zeisberg (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Medicine 9, 964-968

96M. Kondo (2004) A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation. Cell Death and Differentiation 11, 1092-1101

97M. Kowanetz (2004) Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein. Molecular and Cellular Biology 24, 4241-4254

98S. Saika (2006) Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. American Journal of Physiology – Cell Physiology 290, C282-289

99U. Valcourt (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Molecular Biology of the Cell 16, 1987-2002

100M. Zeisberg , A.A. Shah and R. Kalluri (2005) Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry 280, 8094-8100

101S. Wang (2003) Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney International 63, 2037-2049

102J. Yang , C. Dai and Y. Liu (2005) A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. Journal of the American Society of Nephrology 16, 68-78

103C. Dai (2004) Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. Journal of the American Society of Nephrology 15, 2637-2647

104J.M. Cruzado (2004) Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes 53, 1119-1127

105V. Brinkmann (1995) Hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells. Journal of Cell Biology 131, 1573-1586

106K.M. Weidner (1990) Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. Journal of Cell Biology 111, 2097-2108

107P. Savagner , K.M. Yamada and J.P. Thiery (1997) The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. Journal of Cell Biology 137, 1403-1419

108J. Zavadil (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proceedings of the National Academy of Sciences of the United States of America 98, 6686-6691

109A. Eger (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24, 2375-2385

110J. Comijn (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Molecular Cell 7, 1267-1278

111M. Guarino , A. Tosoni and M. Nebuloni (2009) Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Human Pathology 40, 1365-1376

112S. Cheng (2006) Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB Journal 20, 1898-1900

113A. Boutet (2006) Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. EMBO Journal 25, 5603-5613

114N. Marcussen (2000) Tubulointerstitial damage leads to atubular glomeruli: significance and possible role in progression. Nephrology Dialysis Transplantation 15 (Suppl 6), 74-75

115M.E. Pagtalunan (1996) Atubular glomeruli in patients with chronic allograft rejection. Transplantation 61, 1166-1171

116M.C. Thomas , W.C. Burns and M.E. Cooper (2005) Tubular changes in early diabetic nephropathy. Advances in Chronic Kidney Disease 12, 177-186

117J. Chalmers and M.E. Cooper (2008) UKPDS and the legacy effect. New England Journal of Medicine 359, 1618-1620

118R.R. Holman (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 359, 1577-1589

119R.R. Holman (2008) Long-term follow-up after tight control of blood pressure in type 2 diabetes. New England Journal of Medicine 359, 1565-1576

120A. Ceriello , M.A. Ihnat and J.E. Thorpe (2009) Clinical review 2: The “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? Journal of Clinical Endocrinology and Metabolism 94, 410-415

121J. Song (2007) EMT or apoptosis: a decision for TGF-beta. Cell Research 17, 289-290

Y. Liu (2010) New insights into epithelial-mesenchymal transition in kidney fibrosis. Journal of the American Society of Nephrology 21, 212-222

C.E. Runyan (2009) Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype. Journal of Biological Chemistry 284, 25181-25189

O. Larsson (2008) Fibrotic myofibroblasts manifest genome-wide derangements of translational control. PLoS One 3, e3220

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