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Commentary |
From the Center for Pediatric Urology and Minimally Invasive Urologic Surgery, Weill Medical College of Cornell University, New York, New York
Interstitial fibrosis is characteristic of many clinical entities including diabetes, ureteral obstruction, transplant rejection, and glomerulonephritis.1 The interstitial fibrosis that accompanies renal disease is a complex process involving derangements in both the synthesis and degradation of collagen and other extracellular matrix proteins. Cellular sources of the extracellular matrix laid down during the development of interstitial fibrosis include fibroblasts and infiltrating macrophages.1 The fibroblasts may be resident renal fibroblasts, fibroblasts that migrate into the kidney from external sources, or a specialized population of fibroblasts known as myofibroblasts.2 Furthermore, recent evidence suggests that during renal injury, renal epithelial cells may transform into fibroblasts in a process known as epithelial-mesenchymal transdifferentiation (EMT).3,4 The synthesis and processing of extracellular matrix that malfunction in fibrosis are under the complex control of many cytokines and other factors.1 One cytokine in particular that has been implicated in fibrotic disease, both in the kidney and in other tissues, is transforming growth factor-ß (TGF-ß).
In the accompanying article "Renal Fibrosis: Collagen Composition and Assembly Regulates Epithelial-Mesenchymal Transdifferentiation," by Zeisberg and colleagues5 in this issue of The American Journal of Pathology, Zeisberg and co-workers use murine renal cell lines in culture to demonstrate that the integrity of basement membrane collagen has a significant effect on EMT in vitro. They further demonstrate that when basement membrane assembly is disrupted, the production of TGF-ß is up-regulated. In this article we will discuss the emerging role of EMT in fibrosis and its regulation, both in vitro and in vivo, with emphasis on effects of TGF-ß and collagen IV.
TGF-ß
TGF-ß is a multifunctional cytokine that has been extensively studied in fibrotic disease.6 It is found in three isoforms (TGF-ß1, TGF-ß2, and TGF-ß3) in most mammalian tissues, which are encoded by three separate genes. TGF-ß acts by binding to three high-affinity receptors known as types I, II, and III.7 TGF-ß either binds directly to the type II receptor, or binds to the type III receptor, which in turn binds to the type II receptor. TGF-ß complexed to the type II receptor then binds to the type I receptor. TGF-ß bound to the type I receptor then phosphorylates transcription factors known as Smads, which translocate to the nucleus and result in multiple effects.8
In addition to its role in renal fibrosis, TGF-ß has a myriad of biological effects including cell proliferation and differentiation, immune regulation, and effects on inflammation. A description of these activities is beyond the scope of this commentary, but they have been covered recently in a symposium6,8,9 and in other reviews.10,11
The Role of TGF-ß in EMT
Transdifferentiation is the process by which cells lose one phenotype and acquire a new one.3,12 Cells may transform from epithelium to mesenchyme (EMT) or from mesenchyme to epithelium. These transformations are active in many tissues and are a part of both normal development and disease processes.
In the primitive chordate, the major tissue type is epithelium. By adopting a mesenchymal phenotype, cells can invade the extracellular matrix which is between epithelia, and can thereby increase their distribution to different parts of the body.3 Subsequently, both mesenchymal to epithelial transdifferentiation and EMT are active in many tissues.
There are many cytokines, growth factors, and adhesion molecules that are involved in these processes.3,12 TGF-ß has been implicated in EMT in several different tissues. The approaches taken to understanding TGF-ß’s role in these systems may be useful in studies on EMT in fibrosis.
In the heart, the endothelial cells that line the lumen of the heart are transformed to mesenchymal cells, which then invade the underlying extracellular matrix leading to subsequent cardiac valve formation. TGF-ß-induced EMT is blocked by antibodies to TGF-ß type II and type III receptors, as well by antisense oligonucleotides to TGF-ß3.13-15
In palatal fusion, median edge epithelial cells transform to mesenchyme.16 In knockout experiments it has been shown that TGF-ß3 is essential to this process.17 Furthermore, it was shown that all palatal epithelia express TGF-ß3 and the TGF-ß type I and II receptors, yet only the median edge cells undergo EMT. Recent studies18 demonstrated that the TGF-ß type III receptor was temporally and spatially restricted only to those cells that undergo EMT. Not only does this provide an explanation for the selectivity of the EMT process, but it also suggests an important role for the TGF-ß type III receptor that is usually described as a nonsignaling receptor.
EMT is also involved in tumorigenesis.3,19 The ability of mature epithelial cells to acquire a mesenchymal phenotype can increase their ability to invade the extracellular matrix. This contributes to their ability to metastasize throughout the body. The invasiveness of several tumor lines from different organs has been correlated with the loss of epithelial markers.20
TGF-ß’s effects on cell growth and differentiation, as well as its
immunosuppressive actions, contribute to its
tumorigenicity.10,11
Moreover, its ability to induce EMT
adds to this effect. Two examples are given here. In murine skin
carcinoma, TGF-ß is essential to the transformation of keratinocytes
into a spindle shape.21
In mammary epithelial cells it has
been shown that TGF-ß stimulation results in EMT,22
as
shown in Figure 1
. Recent studies have
begun to more specifically detail this process. In NMuMG breast
epithelial cells, various constructs have been used to demonstrate that
TGF-ß type I receptor/ALK-5 is essential to TGF-ß-induced EMT and
that Smad 2 or Smad3 mediates the TGF-ß response.23
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In contrast to the detailed description of the role of TGF-ß’s isoforms and its receptor subtypes in EMT in development and carcinogenesis, the role of TGF-ß in the EMT of renal fibrosis is not as well defined.
In vitro, it has been shown that tubule cells can be
transformed into cells with a myofibroblastic phenotype. Fan and
colleagues24
have demonstrated that incubation of NRK-52E
cells, a normal rat kidney epithelial cell line that is commercially
available, with varying doses of TGF-ß caused the following changes:
1) the typical cobblestone appearance of cells in culture was replaced
by the elongated spindle shape associated with fibroblasts. 2) Using
scanning electron microscopy, the cells were shown to lose their
apical-basal polarity and cell surface microvilli. The apical-basal
polarity was replaced by a front end-back end fibroblast-like polarity
with cytoplasmic projections at the front end. 3) Under transmission
electron microscopy, large bundles of actin microfilaments and dense
bodies were seen. 4) The presence of 
-smooth muscle actin in the
TGF-ß-transformed cells was confirmed by immunohistochemistry,
Western blot, and flow cytometry. 5) There was a loss of the epithelial
antigen, E-cadherin. Moreover, Fan and colleagues24
illustrated that these effects were blocked by a neutralizing antibody
to TGF-ß, suggesting that they are indeed TGF-ß-dependent.
Similar studies25
using interleukin-1 have shown that it,
too, can transform NRK-52E cells into cells with a fibroblastic
appearance. These transdifferentiated cells express -smooth muscle
actin and have diminished expression of E-cadherin. Addition of
neutralizing antibody to TGF-ß blocked the effects of interleukin-1
on EMT, once again suggesting TGF-ß dependence.
Fibroblast-Specific Protein as a Fibroblast Marker
Although the previously described combinations of antigen expression and cell shape changes have been used to document EMT, there is a lack of specificity in the antigens used to characterize the transformed cells as fibroblasts. Strutz and colleagues4 sought to find a marker that would be specific for fibroblasts. Using subtractive and differential hybridization techniques, they compared murine epithelial and fibroblast cell lines. A differentially expressed protein was subsequently characterized and named fibroblast-specific protein-1 (FSP-1). By Northern blot analysis, FSP-1 was found to be expressed in fibroblast cell lines, but not expressed in other cell lines such as renal proximal tubular cells, mesangial cells, endothelial cells, or hepatocytes. In addition, when a polyclonal antibody was directed against FSP-1, FSP could be detected in fibroblast cell lines, but not in renal tubular cell lines.
When epithelial cells were transfected with FSP-1, there was a change in morphology to a stellate and elongated shape, characteristic of fibroblasts. In addition, when epithelial cells were grown in collagen gels, they began to express vimentin ( a mesenchymal marker), and FSP-1, and lost the ability to express keratin.4
Further evidence of FSP-1 as a specific fibroblast marker was demonstrated when Okada and colleagues26 showed in vitro that MCT cells (a renal proximal tubular cell line) incubated with TGF-ß or with a combination of TGF-ß and epidermal growth factor showed morphological changes consistent with EMT. In addition, cytokeratin and Z-01 (a marker for epithelial cell tight junctions) were lost, and vimentin was expressed. Along with transdifferentiation, FSP-1 was expressed in these cells. Treatment of cells with FSP-1 antisense oligomers suppressed de novo expression of FSP-1 and concomitant changes in morphology, collagen synthesis, and decreased cytokeratin expression. FSP-1 is now being used to examine EMT in vivo in renal fibrosis models.
Effects of TGF-ß on Renal Tubular EMT in Vivo
The demonstration of EMT in vivo in fibrosis has been
more challenging than its in vitro characterization.
However, Okada and colleagues27
have attempted to
demonstrate in vivo EMT using an immunohistochemical
approach. In their studies they examined expression of the epithelial
marker cytokeratin, FSP-1, and HSP47, a marker for collagen synthesis.
They used DBA/2-pcy mice that exhibit progressive renal cyst formation,
and which may serve as a model for polycystic kidney disease. In
control DBA/2-pcy mice, cytokeratin was visualized in normal tubules.
As the disease progressed, epithelial cells in remnant tubules, which
were trapped within fibrotic septa around adjacent cysts, expressed
FSP1 and HSP47, and lost expression of cytokeratin. Because
FSP1-positive cells were in remnant tubules, it was inferred that EMT
had taken place. The demonstration of HSP47 positivity in these cells
further suggested the fibroblastic function of collagen synthesis. Of
additional interest was their finding that -smooth muscle actin was
not co-expressed with FSP-1 or HSP. Thus contrary to
others2,28
who have shown an up-regulation of -smooth
muscle actin in fibrotic states, Okada and colleagues27
were able to demonstrate a transdifferentiation of epithelium to
fibroblasts, but not a transdifferentiation of epithelium to
myofibroblasts.
In another approach to demonstrating EMT in vivo,
Dautheville and colleagues29
presented a study in which
transgenic mice were produced with a lacZ reporter gene downstream of a
large segment of pro-2 collagen promoter. Thus collagen synthesis
was coupled to lacZ expression. In unobstructed murine kidneys, the
relative absence of LacZ expression indicated minimal levels of
collagen synthesis. However, kidneys subjected to 2 weeks of unilateral
ureteral obstruction exhibited two lacZ-positive cell populations. One
population was in the interstitium, and some of those cells had the
shape of fibroblasts. The second lacZ-positive population was comprised
of tubular epithelial cells. These results suggest that epithelial
cells in unilateral ureteral obstruction can synthesize collagen, which
would indicate some degree of EMT.
In a fibrotic model produced by 5/6 nephrectomy, Ng and
colleagues30
have used morphological and antigen markers
to assess EMT. At 3 weeks after nephrectomy, -smooth muscle actin
was expressed in renal tubular epithelial cells. Ultrastructurally,
actin filaments and dense bodies were present in the epithelial cells,
corroborating the EMT (although in this case it seems to be an
epithelial to myofibroblast transdifferentiation). As the experiment
progressed, the epithelial cells lost their apical-basal polarity and
became elongated. Of interest to the concurrently published article by
Zeisberg and colleagues,5
expression of -smooth muscle
actin was associated with disruption of the tubular basement membrane.
Furthermore, the transformed cells appeared to migrate into the
peritubular interstitium through the damaged basement membrane.
Indeed, Zeisberg and colleagues5 suggest that basement membrane integrity regulates EMT via a TGF-ß-dependent mechanism. We now turn our attention to basement membranes, with a focus on collagen IV. We shall briefly explore the physiological roles and molecular compositions of these structures in an effort to better understand their roles in EMT and renal interstitial fibrosis.
Basement Membranes
Basement membranes are specializations of extracellular matrix that separate epithelia, endothelia, peripheral nerves, muscle cells, and adipose cells from the supporting stroma. As such, basement membranes comprise the immediate microenvironment in which parenchyma exists. They are composed of a complex network of collagen IV, laminin, entactin/nidogen, and sulfate proteoglycans.31 Although the role and importance of basement membranes as a scaffolding are well understood, their roles in cellular signaling and EMT are only recently beginning to be elucidated.
The Role of Collagen IV in Basement Membranes
Collagen IV is the main structural protein found in basement
membranes. Six homologous peptides, designated 1(IV) through
6(IV), have been identified as the chains that assemble to form the
collagen IV protomer. The genes for 1(IV) and 2(IV) exist
pairwise in a head-to-head manner on chromosome 13 in
humans.32
The 3(IV) and 4(IV) gene loci are
positioned similarly on chromosome 2, with the 5(IV) and 6(IV)
genes located on the X chromosome.33
Each chain is
1400 residues in length. The collagenous portion of the polypeptide
is comprised of a series of Gly-X-Y triplets, and is interrupted by
20 short noncollagenous sequences. The carboxyl terminus is a 230
residue globular domain designated NC1 (noncollagenous 1) that has been
demonstrated to direct protomer assembly.34
Three chains associate via NC1 interactions, after which their
collagenous domains fold into triple helices through covalent and
noncovalent interactions to yield the trimeric collagen IV
protomer.33,35-37
The collagen IV protomer is divided
into three regions: an amino terminus 7S domain, a middle
triple-helical domain, and a carboxyl terminus NC1
domain33,36,37
that is globular, noncollagenous, and
comprised of the individual NC1 domains of the component chains.
Protomers dimerize via head-to-head interactions of their NC1
carboxy-terminal domains to yield hexamers and/or tetramerize via their
7S regions to yield a complex meshwork (Figure 2)
.38
The six (IV) chains
enable assembly of 56 distinct protomers. The diversity of protomer
phenotype enables tissue-specific expression of unique basement
membrane networks.31
|
3(IV) through 6(IV)
have been identified in human distal tubular basement membranes, in
contrast to proximal tubule that contains only 1(IV)/2(IV)
protomers.31
Bowman’s capsular basement membrane is
composed of protomers containing 1(IV), 2(IV), 5(IV), and
6(IV).31
The glomerular basement membrane is composed
of two specific networks. The major protomeric subtype present in the
mature glomerulus is a thick subepithelial network composed of
3(IV)/4(IV)/5(IV) protomers. The minor network, thin and
located subendothelially, is an embryological remnant of the glomerular
precursor network composed of 1(IV)/2(IV)
protomers.31,39
Segment-specific heterogeneity of collagen IV protomer expression in
the nephron hints at dynamic and complex function in renal cellular
physiology. In the accompanying article, Zeisberg and
colleagues5
clearly demonstrate that collagen IV plays a
regulatory role in EMT. By incubating mouse proximal tubular epithelial
cells (MCT) with recombinant 1NC1, Zeisberg and colleagues effected
the transdifferentiation of MCT cells to cells of fibroblast-like
morphology. The transdifferentiated cells exhibited increased
expression of FSP-1 and vimentin, showed decreased cytokeratin
expression, and became spindle-shaped. Northern blot assay revealed
that the transdifferentiation coincided with increased expression of
mRNA for TGF-ß1 and that the transdifferentiation could be blocked by
anti-TGF-ß1 antibodies.5
The Interplay between TGF-ß and Basement Membrane Integrity
In addition to its other functions discussed in this review, TGF-ß1 regulates basement membrane integrity. Ultrastructural analysis of the effect of TGF-ß1 on basement membrane formation by immortalized type II alveolar epithelial cells in vitro has revealed that basement membrane formation depends on TGF-ß1.40 However, increasing the level of TGF-ß1 beyond a threshold level causes discontinuous basement membrane formation, despite increased expression of the basement membrane component molecules. Excessive production of basement membrane components is thought to obstruct their integration into a continuous basement membrane.40
Furthermore, TGF-ß up-regulates expression of the 92- and 72-kd type
IV collagenases, MMP-9 and MMP-2.41
MMP-9 and MMP-2
therefore likely play a role in TGF-ß-mediated basement membrane
disruption. Indeed, MMP-2 activity has been demonstrated to be crucial
for EMT in avian cardiogenesis. By antagonizing MMP-2, Song and
colleagues42
were able to impede the transdifferentiation
of endocardial cells to mesenchyme. Furthermore, they
demonstrated that MMP-2-mediated proteolytic alteration of type IV
collagen is important for the migration of transdifferentiated cells.
Moreover, TGF-ß1 up-regulates expression of collagen I, which induces
MMP-9 synthesis43
and stabilizes the mesenchymal
phenotype.5
Disruption of basement membrane integrity and
increased TGF-ß1 expression thus seem to interact in an autocrine,
positive feedback loop that drives EMT (Figure 3)
.5
|
1NC1 domain effects an
in vitro increase in levels of TGF-ß1 is unknown. Zeisberg
and colleagues5
hypothesize that without a collagenous
domain, recombinant 1NC1 exerts a dominant-negative effect by
disrupting helix formation in any protomer or protomeric dimer in which
it is incorporated. They use FLAG-tagging to demonstrate that the
recombinant 1NC1 becomes incorporated into protomers. The resultant
incomplete collagen IV molecules are presumably degraded. This insult
to basement membrane integrity is thought to trigger a cascade that
up-regulates expression of TGF-ß1. The notion that recombinant
1NC1 induces TGF-ß1 indirectly via disruption of basement membrane
integrity is supported by an increase in collagen IV degradation
products in the supernatants taken from 1NC1-treated cell cultures.
In addition to the elegant experiments presented in the accompanying
paper by Zeisberg and colleagues,5
recent studies have
demonstrated other novel actions of NC1 that may be relevant to EMT.
Collagen IV NC1 domains have been shown to be integrin
ligands.38
The integrins are a family of transmembrane
heterodimeric receptors capable of initiating signaling cascades via
the inositol phospholipid pathway or tyrosine
phosphorylation.44
Petitclerc and
colleagues’38
work with monoclonal antibodies and human
endothelial cells reveals that 2NC1 ligates with vß3 integrin,
as well as with integrin vß5 and the ß1 integrins. 3NC1 and
6NC1 interact with vß3, but not with the ß1 integrins.
Systemic administration of 2NC1, 3NC1, and 6NC1 inhibit
cytokine-induced angiogenesis and tumor growth in CAMs of chick
embryos. The underlying mechanism by which 1NC1 induces TGF-ß1 is
likely complex and warrants further investigation.
EMT, TGF-ß, and Basement Membranes: Implications for Renal Fibrosis
The final outcome of many types of injury to the kidney is interstitial fibrosis. It is already clear that the fibrotic process is accompanied by changes in the cellular composition of the kidney, as well as the cytokine milieu. Evidence has accumulated throughout the last several years that TGF-ß is a key cytokine in this process. Experimental overexpression of TGF-ß results in fibrosis, and overexpression of TGF-ß in clinical and experimental renal disease has been documented. Both antisense and antibodies to TGF-ß have been shown to ameliorate fibrosis in experimental renal models of unilateral ureteral obstruction, diabetes, and glomerulonephritis.45-51
The interplay between basement membrane integrity, TGF-ß1, and EMT
and resulting renal fibrosis has yet to be fully elucidated. Of
interest, however, are the findings in Alport syndrome, which is
characterized by progressive glomerulonephritis that culminates in
fibrosis and renal failure.52,53
This loss of renal
function results from the absence of a functional 3(IV), 4(IV),
or 5(IV) gene. Alport patients cannot synthesize the
3(IV)/4(IV)/5(IV) protomeric network of the mature glomerulus.
They therefore retain the embryonic 1/2(IV) network phenotype,
which appears normal at the onset of life but deteriorates throughout
time, explaining the delayed onset, progressive course of Alport
syndrome.31
Although the mechanism of damage to the
glomerular basement membrane is not fully understood, TGF-ß1 has been
implicated. Alport renal disease progression has been shown to induce
TGF-ß1 in humans and mice.53
Furthermore, in the murine
model of Alport disease, damage to the glomerular basement membrane is
ameliorated by the administration of TGF-ß soluble
receptor.52
Given that Alport syndrome involves
TGF-ß1-dependent fibrosis and disruption of the glomerular basement
membrane, it is possible that EMT contributes to its pathogenesis.
Conclusion
The current studies suggest a broader role for TGF-ß in fibrosis. In addition to its previously documented effects on collagen synthesis and degradation, TGF-ß’s effects on EMT and basement membrane integrity likely contribute to its profibrotic actions. Although this review has focused on TGF-ß, the molecular mechanisms behind EMT are not yet clear enough to rule out TGF-ß-independent transdifferentiation pathways. Regardless, EMT has emerged as a very likely contributor to renal interstitial fibrosis. Furthermore, Zeisberg and colleagues5 have clearly demonstrated that disruption of basement membrane integrity up-regulates EMT in a TGF-ß-dependent mechanism.
Although our understanding of the pathogenesis of renal fibrosis is incomplete, the important experimental work reviewed herein suggests novel anti-fibrotic therapeutic approaches. In addition to targeting TGF-ß directly, strategies focused on basement membrane stabilization, inhibition of type IV collagenases, or direct suppression of EMT may well prove effective in combating renal interstitial fibrosis.
Footnotes
Address reprint requests to Dr. Diane Felsen, Weill Medical College of Cornell University, Dept. of Urology, 1300 York Ave., New York, NY 10021-4896. E-mail: dfelsen{at}med.cornell.edu
Accepted for publication August 1, 2001.
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