Abstract
Epithelial-to-mesenchymal transition (EMT) involving injured epithelial cells plays an important role in the progression of fibrosis in the kidney. Tubular epithelial cells can acquire a mesenchymal phenotype, and enhanced migratory capacity enabling them to transit from the renal tubular microenvironment into the interstitial space and escape potential apoptotic cell death. EMT is a major contributor to the pathogenesis of renal fibrosis, as it leads to a substantial increase in the number of myofibroblasts, leading to tubular atrophy. However, recent findings suggest that EMT involving tubular epithelial cell is a reversible process, potentially determined by the surviving cells to facilitate the repopulation of injured tubules with new functional epithelia. Major regulators of renal epithelial cell plasticity in the kidney are two multifunctional growth factors, bone morphogenic protein-7 (BMP-7) and transforming growth factor β1 (TGF-β1). While TGF-β1 is a well-established inducer of EMT involving renal tubular epithelial cells, BMP-7 reverses EMT by directly counteracting TGF-β-induced Smad-dependent cell signaling in renal tubular epithelial cells. Such antagonism results in the repair of injured kidneys, suggesting that modulation of epithelial cell plasticity has therapeutic advantages.
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Introduction
Chronic progressive fibrosis of the kidney remains an unsolved challenge for nephrologists, as it still almost inevitably leads to end-stage renal failure, requiring replacement therapy [1, 2]. Scarring of the kidney, which is caused by a progressive fibrosis leading to impairment of kidney function, occurs due to a variety of primary insults, such as diabetes mellitus, hypertension, primary glomerulopathies, autoimmune diseases, toxic injury or congenital abnormalities [1, 3, 4]. Scarred kidneys are almost uniformly characterized by the triad of glomerulosclerosis, interstitial fibrosis and tubular atrophy, implicating common mechanisms which are independent of the underlying primary disease [1, 4]. While resident renal fibroblasts are traditionally considered to be the principal mediators of renal fibrosis, recent studies have highlighted the involvement of tubular epithelial cells, the epithelial parenchyme of the kidney, in progression of chronic renal disease [1, 3]. Tubular epithelial cells possess a unique plasticity, which enables them to convert between the epithelial and mesenchymal phenotypes [5, 6]. While specific therapeutic options to inhibit progression of chronic renal disease are still not available in the clinic, modulation of epithelial-to-mesenchymal transition (EMT) offers a novel therapeutic target to potentially inhibit renal fibrogenesis.
The epithelial-to-mesenchymal transition
EMT is necessary for embryonic development, tumor progression and organ fibrosis [7, 8]. During EMT, epithelial characteristics are lost and a mesenchymal phenotype is acquired [7]. The cell morphology changes from a cuboidal to a fibroblastic shape and intercellular epithelial adhesion molecules such as E-cadherin and zonula occludentes protein ZO-1 are replaced by mesenchymal cytoskeletal markers such as fibroblast-specific protein 1 (FSP1) and vimentin [7, 9, 10]. Instead of interacting with the extracellular matrix (ECM) at the basal cell surface, the transdifferentiated cells acquire the ability to invade the ECM [7, 11].
Plasticity resulting in cells shifting between epithelial and mesenchymal phenotypes is essential in embryonic development as it permits anchored epithelial cells to re-orient in a developing organism [12]. In this regard, EMT is known to contribute to the formation of mesoderm during gastrulation and also to the formation of connective tissue from somitic epithelium [13, 14]. In adults, EMT is speculated to occur involving resident epithelia in response to injury, as an additional source of myofibroblasts/fibroblasts which are essential for repair of injured tissue [14, 15]. During kidney fibrosis however, enhanced conversion of renal tubular epithelial cells into myofibroblasts/fibroblasts is considered unfavorable, as it leads to disruption of polarized renal tubular epithelial layers and an increase in fibrotic scar formation [15].
The EMT in the kidney
In recent years, EMT associated with adult injured kidneys has become of increasing interest. Initial reports have demonstrated that FSP1 (S1004A), a member of the S100 family of calcium-binding proteins exclusively expressed in fibroblasts, can be detected in tubular cells of injured kidneys in both acute and chronic disease [16]. This finding has been confirmed by numerous independent studies, which have detected renal tubular epithelial cells in the process of EMT in different animal models of chronic renal disease and also in human kidney biopsies [15, 16, 17, 18, 19, 20, 21]. A reciprocal correlation of increasing numbers of tubular epithelial cells involved in EMT and a decline of excretory renal function suggests a pathogenic role for the EMT in the progression of chronic renal disease [5]. By utilizing a model of γGT-LacZ transgenic mice, which allows the indisputable identification of cells derived from proximal tubular epithelium in the kidney, Iwano et al. have recently demonstrated that more than one third of renal interstitial fibroblasts, the main mediators of renal interstitial fibrosis, are derived from renal tubular epithelium via EMT [15]. Further evidence for the importance of the EMT in the progression of chronic renal disease has been provided by the observation that reversal of EMT results in improvement of renal function and decreased mortality in a mouse model of crescentic glomerulonephritis [5].
A model for EMT in the kidney
Mechanistic insights into the regulation of EMT involving renal tubular epithelial cells are predominantly based on in vitro studies. The main inducers of EMT in renal tubular epithelial cells can be categorized into growth factors and enzymes, which facilitate disruption of the tubular basement membrane integrity [3, 10, 22, 23]. Transforming growth factor β1 (TGF-β1) has been identified as the main inducer of EMT in the kidney and in other organ systems [8, 24, 25, 26]. Growth factors with a capacity to induce EMT of tubular epithelial cells also include epithelial growth factor (EGF), basic fibroblast growth factor (bFGF) and Interleukin-1 (IL-1) [9, 22, 27]. In addition to stimulation by growth factors, disruption of the underlying tubular basement membrane (TBM) by MMP-2 or other MMPs, can induce EMT of tubular epithelial cells [10, 28]. The main inducers of EMT, TGF-β1 and disruption of the TBM, can also promote cell death via apoptosis (TGF-β1) or anoikis (disruption of the TBM), suggesting that EMT serves as a physiologic pathway that allows injured tubular epithelial cells to escape cell death [29, 30, 31]. Hence, EMT-derived fibroblasts can facilitate immediate repair of injury and potentially also serve as a pool of vital cells with capacity to repopulate the injured tubular epithelium [5, 15]. This concept is strengthened by the observation that constant exposure of tubular epithelial cells to TGF-β1 induces apoptosis in a substantial number of cells, while the remaining cells, which survive, undergo EMT [32, 33]. Based on these findings, a hypothetical model of EMT in chronic renal disease is proposed (Fig. 1). In the normal kidney, tubular epithelial cells are tightly connected with their neighboring cells via intercellular adhesion molecules such as E-cadherin [24]. On their basal side they interact with the TBM, while the apical side faces the tubular lumen [24]. In the initial phases of renal tubular injury, the epithelial cells initially respond to TGF-β1 and/or MMP-2 (which are potentially released by infiltrating mononuclear cells) by acquiring an “activated” state [6]. If the pathogenic insult persists, activated tubular epithelial cells can either die or undergo EMT [6]. The process of EMT, which includes various intermediate stages, is initiated by loss of E-cadherin expression and autocrine TGF-β1 and MMP-2 secretion, which further facilitate degradation of the TBM and enhance the EMT [6]. Cells derived via EMT then acquire a migratory capacity and traverse across the disrupted TBM into the interstitial microenvironment exhibiting features of a mesenchymal phenotype [19, 23]. EMT-derived fibroblasts within the interstitium contribute to progression of chronic renal disease by deposition of interstitial ECM [34]. EMT and apoptosis both contribute to loss of tubular epithelium, leading to tubular atrophy and disease progression.
The role of E-cadherin in EMT during renal fibrosis
While numerous distinct signaling pathways have been described as initiators of EMT in different settings, all of them culminate in the loss of E-cadherin [24, 35, 36]. E-cadherin is an epithelial cell specific intercellular adhesion molecule, which by itself can induce mesenchymal-to-epithelial transition (MET), when overexpressed in cells of mesenchymal lineage [37]. Several different studies have demonstrated that E-cadherin is an important determinant for maintenance of the epithelial phenotype [5, 38, 39]. Metastatic cancers are associated with loss of E-cadherin [40]. In many different carcinoma cell lines E-cadherin functions as a suppressor of invasiveness [41]. Several studies demonstrate that loss of cell-cell adhesion is due to decreased E-cadherin expression [42]. Identification of the transcriptional regulators of E-cadherin, such as Snail and SIP1, have further revealed the importance of E-cadherin expression for EMT and a possible role in the progression of cancer [43, 44, 45]. Furthermore, the conversion of an epithelial cell into a fibroblast, with its numerous intermediate stages, is reflected by a reciprocal expression of E-cadherin and FSP1. E-cadherin expression gradually decreases while FSP1 expression increases inversely [5, 46]. Such studies have led to the speculation that E-cadherin is a potential epithelial master gene [24, 47].
Plasticity of renal tubular epithelium
EMT in adult kidneys is associated with reiteration of renal developmental programs [48]. While most parenchymal epithelia are derived via branching from a primary epithelial sheet, the renal epithelium has two distinct embryological origins [49]. Most of the epithelium, which constitutes the nephron (from glomerulus to connecting tubule) is derived from the mesenchymal blastema, whereas the segment starting at the collecting tubule stems from the epithelial Wolffian duct [50]. Conversion of the metanephric mesenchyme into epithelium via MET is the central mechanism during kidney development [49, 51]. Formation of the epithelial nephron is initiated when the ureteric bud epithelium invades the mesenchymal blastema [50]. Condensing mesenchyme then adheres and forms an epithelial cyst, associated with expression of basement membrane proteins and formation of a lumen [52]. The growth factor BMP-7 plays an important role in regulation of nephrogenesis associated with MET, while TGF-β1 has been demonstrated to inhibit branching morphogenesis in the developing kidney [53, 54]. Interestingly, EMT in the injured adult kidney occurs in cells which are originally of MET-derived lineage [48]. In adult tubular epithelial cells which undergo EMT basal BMP-7 expression is substantially decreased, whereas expression of TGF-β1, the main inducer of EMT, is enhanced [5]. It was recently demonstrated that administration of BMP-7 can reverse TGF-β1-induced EMT in adult tubular epithelial cells, suggesting that these cells maintained their capacity for transition back to renal tubular epithelial cells [5]. In summary, these findings suggest that the tubular epithelium, due to its unique mesenchymal origin, is plastic enough to acquire mesenchymal or epithelial phenotypes in disease and during repair. TGF-β1 and BMP-7, both members of the TGF-β superfamily, are increasingly being recognized as mutual antagonists in the kidney [5].
Bone morphogenic protein-7
Bone morphogenic proteins (BMPs) are a major subgroup of the TGF-β superfamily [55]. BMPs share high homology with activins and TGF-β proteins at the carboxy terminal domain [53]. Traditionally, BMPs are classified into three groups [55]. The first group contains BMP-2 and BMP-4, the second contains BMP-5, BMP-6 and BMP-7, and the third contains BMP-3 and BMP-8 [55]. BMPs in general control morphogenic pathways at different stages of development [56]. The cellular responses to BMP are mediated by type I and type II cell surface transmembrane serine/threonine kinase receptors [57, 58, 59].
BMP-7, also sometimes referred to as osteogenic protein-1 (OP-1), was originally identified as a potent osteogenic factor purified from bone [60]. Different studies have demonstrated a role for BMP-7 during mammalian kidney development [61, 62]. BMP-7 binds to the ALK3 and ALK6 type I serine/threonine kinase receptors [59, 63]. BMP-7 and its receptors are expressed in regions associated with mesenchymal-epithelial tissue interactions [64]. Homozygous BMP-7-deficient mice have dysplastic kidneys and die shortly after birth from renal failure [61, 62]. In these mutants, formation of S-shaped tubules is initiated, but is arrested at embryonic ~day 11.5 [61, 62]. BMP-7 regulates branching morphogenesis in the developing kidney, which is associated with MET, and functions as a survival factor for renal epithelium during kidney development [65, 66].
In the adult kidney, BMP-7 is increasingly being recognized for its potential to maintain tubular homeostasis in acute and chronic renal injury [67, 68]. Acute and chronic tubular injury is associated with decreased tubular BMP-7 expression, and administration of exogenous BMP-7 mediated repair of tubular injury and the return of renal function in different models of kidney injury [5, 69, 70, 71, 72, 73]. Tubular injury in chronic renal disease is associated with increased TGF-β1 expression in the kidney [74]. This reciprocal relationship between BMP-7 and TGF-β1 suggests that these two growth factors can function as physiological antagonists in the adult kidney [73]. Renal tubular epithelial cells respond to exposure to TGF-β1 by either undergoing apoptosis or EMT (Fig. 2), which eventually leads to tubular atrophy [6, 9]. While an anti-apoptotic effect of BMP-7 on tubular epithelial cells has not been demonstrated yet, BMP-7 is sufficient to reverse TGF-β1-induced EMT (Fig. 2) [5]. BMP-7 mediated reversal of EMT is independent of persisting TGF-β1 levels, suggesting that these two molecules directly counteract each other’s signaling pathways within the cell [5].
Counteraction of Smad-dependent TGF-β1 signaling by BMP-7 in renal tubular epithelial cells
All members of the TGF-β superfamily signal through heteromeric complexes of transmembrane type I and type II serine/threonine kinase receptors [75, 76]. Within this complex, the type II receptor kinase activates the type I receptor kinase, which subsequently phosphorylates Smad proteins, which function as signal transducers [35, 57, 58, 76]. Smads are subdivided into three classes, the receptor-regulated Smads (Smad1, -2, -3, -5 and -8), the common Smads (Smad4) and the inhibitory Smads (Smad6 and -7) [57]. Members of the TGF-β superfamily activate distinct downstream pathways involving serine/threonine kinase receptors and Smads [35, 58, 76, 77]. Each serine/threonine kinase receptor phosphorylates specific R-Smads [35, 76, 77, 78]. BMP-7 binds to ALK3 and ALK6 type I receptors, which function via Smad1, Smad5 and Smad8, whereas TGF-β1 binds to and ALK5 type I receptors, which activate Smad2 and Smad3 [59, 63] (Fig. 3). The phosphorylated Smad2/3 (TGF-β1 Smads) or Smad1/5/8 (BMP-7 Smads) form a hetero-complex with Smad4 (common Smad), which then shuttles into the nucleus and regulates the transcription of target genes in association with several co-transcriptional regulators (Fig. 3) [59, 63, 79]. While TGF-β1 directly inhibits E-cadherin expression and induces EMT in a Smad3-dependent manner, BMP-7 enhances E-cadherin expression via Smad5 and restores the epithelial phenotype [5, 80]. Such Smad-dependent action by BMP-7 in renal tubular epithelial cells is sufficient to reverse EMT in a mouse model of crescentic glomerulonephritis, resulting into repair of tubular atrophy and improvement of excretory renal function [5]. Direct counteraction between TGF-β1 and BMP-7 activation is unique, as it does not involve extracellular trap-proteins, such as decorin, noggin or nodal [81, 82, 83]. Previously, physiologic negative regulators of TGF-β1 signaling with therapeutic utility have been identified. Soluble proteins such as TGF-β1-binding receptor-traps act by preventing access the receptor. Additionally, the proteoglycan decorin, the circulating protein α2-macroglobulin and the pro-region of the TGF-β1-precursor latency-associated polypeptide (LAP) have been identified as physiological regulators of TGF-β1-action [59]. Decorin has been used with limited toxicity in animal studies to prevent progression of chronic nephropathies [81, 84]. However, inhibition of TGF-β1 activity by decorin ameliorates progression of TGF-β1 induced chronic renal fibrosis, but reversal of disease pathogenesis associated with EMT was not demonstrated, as in the case of BMP-7. While decorin is an ‘extracellular’ competitor of TGF-β1 binding to its receptor its mechanism of action is different in comparison to that of BMP-7 action.
Conclusion
While TGF-β1 has long been identified as the major mediator of renal fibrosis, recent studies have provided increasing evidence that BMP-7 functions as its physiological antagonist in the kidney (Table 1) [5, 85]. BMP-7 is essential for MET-dependent nephrogenesis and branching morphogenesis, while TGF-β1 induces apoptosis of the metanephric mesenchyme and inhibits branching of the ureteric bud [86]. In the adult kidney, increased expression of TGF-β1 is associated with progression of chronic renal disease, while the expression of BMP-7 in the kidney is significantly decreased in injured kidneys [5, 74]. TGF-β1 is the main inducer of EMT in adult tubular epithelial cells, while BMP-7 reverses TGF-β1-induced EMT and restores tubular cell homeostasis [5]. TGF-β1 is a multi-functional growth factor and receptors for BMP-7 are widely distributed throughout the body. Thus, it is important to pursue studies to identify this antagonistic action on a given cell.
Abbreviations
- ALK :
-
Activin-like kinase
- bFGF :
-
Basic fibroblast growth factor
- BMP :
-
Bone morphogenic protein
- ECM :
-
Extracellular matrix
- EGF :
-
Epithelial growth factor
- EMT :
-
Epithelial-to-mesenchymal transition
- FSP1 :
-
Fibroblast specific protein 1
- IL-1 :
-
Interleukin 1
- LAP :
-
Latency-associated polypeptide
- MET :
-
Mesenchymal-to-epithelial transition
- MMP :
-
Matrix metalloproteinase
- TBM :
-
Tubular basement membrane
- TGF :
-
Transforming growth factor
References
Remuzzi G, Bertani T (1998) Pathophysiology of progressive nephropathies. N Engl J Med 339:1448–1456
Pastan S, Bailey J (1998) Dialysis therapy. N Engl J Med 338:1428–1437
Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG (2003) Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 348:2543–2556
Brenner BM (2002) Remission of renal disease: recounting the challenge, acquiring the goal. J Clin Invest 110:1753–1758
Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968
Zeisberg M, Strutz F, Muller GA (2001) Renal fibrosis: an update. Curr Opin Nephrol Hypertens 10:315–320
Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat 154:8–20
Thiery JP (2002) Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2:442–454
Okada H, Danoff TM, Kalluri R, Neilson EG (1997) Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273:F563–574
Zeisberg M, Bonner G, Maeshima Y, Colorado P, Muller GA, Strutz F, Kalluri R (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Pathol 159:1313–1321
Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 23:912–923
Peifer M, McEwen DG (2002) The ballet of morphogenesis: unveiling the hidden choreographers. Cell 109:271–274
Tam PP, Behringer RR (1997) Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68:3–25
Reichmann E, Schwarz H, Deiner EM, Leitner I, Eilers M, Berger J, Busslinger M, Beug H (1992) Activation of an inducible c-FosER fusion protein causes loss of epithelial polarity and triggers epithelial-fibroblastoid cell conversion. Cell 71:1103–1116
Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110:341–350
Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130:393–405
Ng YY, Huang TP, Yang WC, Chen ZP, Yang AH, Mu W, Nikolic-Paterson DJ, Atkins RC, Lan HY (1998) Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Kidney Int 54:864–876
Okada H, Inoue T, Kanno Y, Kobayashi T, Ban S, Kalluri R, Suzuki H (2001) Renal fibroblast-like cells in Goodpasture syndrome rats. Kidney Int 60:597–606
Zeisberg M, Maeshima Y, Mosterman B, Kalluri R (2002) Renal fibrosis: extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am J Pathol 160:2001–2008
Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME (2001) Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 108:1853–1863
Rastaldi MP, Ferrario F, Giardino L, Dell’Antonio G, Grillo C, Grillo P, Strutz F, Muller GA, Colasanti G, D’Amico G (2002) Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 62:137–146
Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 61:1714–1728
Yang J, Liu Y (2001) Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol 159:1465–1475
Hay ED, Zuk A (1995) Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 26:678–690
Miettinen PJ, Ebner R, Lopez AR, Derynck R (1994) TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127:2021–2036
Piek E, Moustakas A, Kurisaki A, Heldin CH, ten Dijke P (1999) TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112:4557–4568
Fan JM, Huang XR, Ng YY, Nikolic-Paterson DJ, Mu W, Atkins RC, Lan HY (2001) Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. Am J Kidney Dis 37:820–831
Cheng S, Lovett DH (2003) Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol 162:1937–1949
Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M (1993) Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 12:3679–3684
Cardone MH, Salvesen GS, Widmann C, Johnson G, Frisch SM (1997) The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 90:315–323
Valdes F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernandez M, Benito M, Nieto MA, Fabregat I (2002) The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res 1:68–78
Anderson RJ, Sponsel HT, Kroll DJ, Jackson S, Breckon R, Hoeffler JP (1994) Escape from the antiproliferative effect of transforming growth factor-beta 1 in LLC-PK1 renal epithelial cells. Kidney Int 45:642–649
Nicolas FJ, Lehmann K, Warne PH, Hill CS, Downward J (2003) Epithelial to mesenchymal transition in Madin-Darby canine kidney cells is accompanied by down-regulation of Smad3 expression, leading to resistance to transforming growth factor-beta-induced growth arrest. J Biol Chem 278:3251–3256
Iwano M, Fischer A, Okada H, Plieth D, Xue C, Danoff TM, Neilson EG (2001) Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol Ther 3:149–159
Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471
Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, Piek E, Bottinger EP (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA 98:6686–6691
Vanderburg CR, Hay ED (1996) E-cadherin transforms embryonic corneal fibroblasts to stratified epithelium with desmosomes. Acta Anat 157:87–104
Tepass U, Truong K, Godt D, Ikura M, Peifer M (2000) Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol 1:91–100
Arias AM (2001) Epithelial mesenchymal interactions in cancer and development. Cell 105:425–431
Birchmeier W (1995) E-cadherin as a tumor (invasion) suppressor gene. Bioessays 17:97–99
Vleminckx K, Vakaet L Jr., Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66:107–119
Potter E, Bergwitz C, Brabant G (1999) The cadherin-catenin system: implications for growth and differentiation of endocrine tissues. Endocr Rev 20:207–239
Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89
Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83
Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E- cadherin and induces invasion. Mol Cell 7:1267–1278
Keirsebilck A, Bonne S, Bruyneel E, Vermassen P, Lukanidin E, Mareel M, van Roy F (1998) E-cadherin and metastasin (mts-1/S100A4) expression levels are inversely regulated in two tumor cell families. Cancer Res 58:4587–4591
Kim K, Lu Z, Hay ED (2002) Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int 26:463–476
Herzlinger D (2002) Renal interstitial fibrosis: remembrance of things past? J Clin Invest 110:305–306
Huber SM, Braun GS, Segerer S, Veh RW, Horster MF (2000) Metanephrogenic mesenchyme-to-epithelium transition induces profound expression changes of ion channels. Am J Physiol Renal Physiol 279:F65–76
Horster MF, Braun GS, Huber SM (1999) Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation. Physiol Rev 79:1157–1191
Herzlinger D, Abramson R, Cohen D (1993) Phenotypic conversions in renal development. J Cell Sci 17:S61–64
Sakurai H, Barros EJ, Tsukamoto T, Barasch J, Nigam SK (1997) An in vitro tubulogenesis system using cell lines derived from the embryonic kidney shows dependence on multiple soluble growth factors. Proc Natl Acad Sci USA 94:6279–6284
Hogan BL (1996) Bone morphogenetic proteins in development. Curr Opin Genet Dev 6:432–438
Sakurai H, Nigam SK (1997) Transforming growth factor-beta selectively inhibits branching morphogenesis but not tubulogenesis. Am J Physiol 272:F139–146
Kingsley DM (1994) The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8:133–146
Ray RP, Wharton KA (2001) Twisted perspective: new insights into extracellular modulation of BMP signaling during development. Cell 104:801–804
Derynck R, Gelbart WM, Harland RM, Heldin CH, Kern SE, Massague J, Melton DA, Mlodzik M, Padgett RW, Roberts AB, Smith J, Thomsen GH, Vogelstein B, Wang XF (1996) Nomenclature: vertebrate mediators of TGFbeta family signals. Cell 87:173
Wrana JL (2000) Regulation of Smad activity. Cell 100:189–192
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700
Ozkaynak E, Rueger DC, Drier EA, Corbett C, Ridge RJ, Sampath TK, Oppermann H (1990) OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J 9:2085–2093
Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9:2795–2807
Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9:2808–2820
Miyazono K, Kusanagi K, Inoue H (2001) Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol 187:265–276
Vukicevic S, Latin V, Chen P, Batorsky R, Reddi AH, Sampath TK (1994) Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affinity binding to basement membranes. Biochem Biophys Res Commun 198:693–700
Piscione TD, Yager TD, Gupta IR, Grinfeld B, Pei Y, Attisano L, Wrana JL, Rosenblum ND (1997) BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis. Am J Physiol 273:F961–975
Vukicevic S, Kopp JB, Luyten FP, Sampath TK (1996) Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci USA 93:9021–9026
Kopp JB (2002) BMP-7 and the proximal tubule. Kidney Int 61:351–352
Kalluri R, Zeisberg M (2003) Exploring the connection between chronic renal fibrosis and bone morphogenic protein-7. Histol Histopathol 18:217–224
Vukicevic S, Basic V, Rogic D, Basic N, Shih MS, Shepard A, Jin D, Dattatreyamurty B, Jones W, Dorai H, Ryan S, Griffiths D, Maliakal J, Jelic M, Pastorcic M, Stavljenic A, Sampath TK (1998) Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J Clin Invest 102:202–214
Wang SN, Lapage J, Hirschberg R (2001) Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol 12:2392–2399
Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 13:S14–21
Wang S, Chen Q, Simon TC, Strebeck F, Chaudhary L, Morrissey J, Liapis H, Klahr S, Hruska KA (2003) Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 63:2037–2049
Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285:F1060–1067
Border WA, Noble NA (1995) Targeting TGF-beta for treatment of disease. Nat Med 1:1000–1001
Attisano L, Wrana JL (2002) Signal transduction by the TGF-beta superfamily. Science 296:1646–1647
Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1:169–178
Derynck R, Zhang Y, Feng XH (1998) Smads: transcriptional activators of TGF-beta responses. Cell 95:737–740
Wrana J, Pawson T (1997) Signal transduction. Mad about SMADs. Nature 388:28–29
Candia AF, Watabe T, Hawley SH, Onichtchouk D, Zhang Y, Derynck R, Niehrs C, Cho KW (1997) Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124:4467–4480
Itoh S, Thorikay M, Kowanetz M, Moustakas A, Itoh F, Heldin CH, ten Dijke P (2003) Elucidation of Smad requirement in transforming growth factor-beta type I receptor-induced responses. J Biol Chem 278:3751–3761
Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E (1992) Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360:361–364
Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT (2003) The BMP antagonist noggin regulates cranial suture fusion. Nature 422:625–629
Yeo C, Whitman M (2001) Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol Cell 7:949–957
Isaka Y, Brees DK, Ikegaya K, Kaneda Y, Imai E, Noble NA, Border WA (1996) Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 2:418–423
Zeisberg M, Ericksen MB, Hamano Y, Neilson EG, Ziyadeh F, Kalluri R (2002) Differential expression of type IV collagen isoforms in rat glomerular endothelial and mesangial cells. Biochem Biophys Res Commun 295:401–407
Schedl A, Hastie ND (2000) Cross-talk in kidney development. Curr Opin Genet Dev 10:543–549
Acknowledgements
The authors are supported by grants DK62987 and DK55001 from the NIH, research funds for the Center for Matrix Biology at the Beth Israel Deaconess Medical Center, the Espinosa Liver Fibrosis Fund, the Stop and Shop Pediatric Brain Tumor Foundation (to M.Z.) and a grant from the Deutsche Forschungsgemeinschaft DFG ZE5231/1 (to M.Z.).
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Zeisberg, M., Kalluri, R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med 82, 175–181 (2004). https://doi.org/10.1007/s00109-003-0517-9
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DOI: https://doi.org/10.1007/s00109-003-0517-9