Division of Kidney Diseases, Department of Pediatrics, The Feinberg School of Medicine of Northwestern University, and Children's Memorial Institute for Education and Research, Chicago, Illinois 60611-3008
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ABSTRACT |
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Transforming growth factor- (TGF-
)
is closely associated with progressive renal fibrosis. Significant
progress has been accomplished in determining the cellular signaling
pathways that are activated by TGF-
. This knowledge is being applied
to glomerular mesangial cell models of extracellular matrix (ECM)
accumulation. A central component of TGF-
-stimulated mesangial cell
fibrogenesis is the TGF-
family-specific Smad signal transduction
pathway. However, while Smads play an important role in collagen
accumulation, recent findings indicate that cross talk among a variety
of pathways is necessary for maximal stimulation of collagen
expression. Further investigation of these multiple interactions will
provide insight into possible ways to interrupt cellular mechanisms of
glomerular fibrogenesis.
transforming growth factor-; glomerulosclerosis; Smads
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INTRODUCTION |
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GLOMERULOSCLEROSIS IS A PROCESS by which normal, functional glomerular tissue is replaced by accumulated deposits of extracellular matrix (ECM). It represents a common pathway for the loss of functioning glomeruli associated with primary diseases as disparate as chronic glomerulonephritis, obstructive uropathy, and retroviral infection (88, 90). In addition, it represents either the cause or the outcome of many cases of steroid-unresponsive nephrotic syndrome. Idiopathic focal segmental glomerulosclerosis is a leading cause of chronic progressive kidney disease and appears to be increasing in incidence in both children (8, 95) and adults (47).
The pathogenesis of glomerulosclerosis is uncertain. It is likely that all three major cells of the glomerulus participate in the fibrotic process. Recently published genetic data (11, 44, 75) and the finding of podocyte abnormalities in transgenic models of glomerulosclerosis (93) or in patients (94) suggest that the visceral epithelial cell plays a significant role. This assertion is supported by earlier data implicating potential epithelial cell stressors such as glomerular hypertension, hyperfiltration, or hypertrophy in sclerosis (12). Some models implicate the endothelial cell in the sclerotic process (4, 53). Still others suggest a role for the mesangial cell (25). This last possibility is attractive because, in many models of glomerulosclerosis (as well as in idiopathic focal segmental glomerulosclerosis, clinically), ECM accumulation often appears to begin in the mesangium. In addition, filtered macromolecules may be trapped in the mesangium, initiating an inflammatory response that could play a role in stimulating ECM synthesis. A unifying hypothesis can be constructed that includes participation by all of the cellular elements of the glomerulus. Glomerular capillary hypertension, or a genetic or acquired abnormality of podocyte adhesion or structure, permits hyperfiltration of macromolecules. Paracrine signals from the injured podocyte stimulate endothelial cell expression of leukocyte adhesion molecules and impair endothelial cell fibrinolytic activity. Signals from epithelial or endothelial cells to the mesangium, or direct delivery of proinflammatory substances through the glomerular filtrate, initiates a process that culminates in the accumulation of ECM (89). Mesangial expansion infringes on the capillary spaces, decreasing filtration surface area in the glomerular tuft.
One aspect of this unfortunate series of events is mesangial
accumulation of ECM. The critical determinant of matrix accumulation is
the balance between ECM synthesis and dissolution (19,
87). This net matrix turnover reflects rates of matrix
production (affected by transcription and translation) or degradation
(determined by synthesis and activity of ECM proteases and their
inhibitors) and factors that affect the susceptibility of the ECM
proteins to degradation, such as glycosylation (102) or
the stability with which these proteins have been incorporated into the
matrix. Recently, efforts have been directed toward modeling the
cellular events regulating glomerular ECM turnover. A variety of
physiological, pharmacological, and molecular approaches has been used
to study how various mediators initiate or modify intracellular
signaling pathways to cause mesangial cell matrix accumulation. These
factors include transforming growth factor (TGF)- (9),
basic fibroblast growth factor (28), platelet-derived
growth factor (28), ANG II (64), connective
tissue growth factor (24), and various eicosanoids
(52). This review will focus primarily on TGF-
.
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TGF-![]() |
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A significant body of literature supports a role for TGF- in
glomerular ECM accumulation. This growth factor is present in human
glomeruli and has been associated with increased mesangial matrix in
several glomerular diseases (109), including diabetic nephropathy (105). Intrarenal infusion of antisense
oligonucleotides to decrease the expression of TGF-
decreases
sclerosis in experimental nephropathy (3). Conversely,
infusion of the TGF-
gene causes sclerosis in rats
(40). Mice transgenic for increased expression of TGF-
develop renal fibrosis (66). These data suggest that TGF-
could play a role in glomerular ECM accumulation in human disease.
However, not all studies have detected elevated levels of TGF- in
the glomerulus in human disease or animal models of glomerulosclerosis. Sclerosis represents the final outcome of a number of initiating events
that could affect the balance in ECM turnover. In addition to disease
heterogeneity, varied data also could reflect the duration of illness.
Thus patients studied late in disease progression could be at a stage
where a TGF-
-mediated process has been supplanted by one mediated by
another factor such as connective tissue growth factor. Nonetheless,
the evidence is strong, albeit circumstantial, that TGF-
plays a
significant role in many cases of glomerulosclerosis.
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TGF-![]() |
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TGF- is a pleiotrophic cytokine that originally was
described as permitting anchorage-independent growth in soft agar
(a model of neoplastic transformation). It was subsequently found to decrease cell division, suppress certain immune responses, and
induce differentiation in some cell types. The mammalian TGF-
s belong to a larger family of similar molecules that includes activin and the bone morphogenetic proteins (BMPs) (59). The most
broadly studied TGF-
, TGF-
1, is secreted as an inactive, 25-kDa
homodimer that is noncovalently associated with a latency-associated
protein (Fig. 1). In some cases, this
complex may be bound to a 125- to 160-kDa latent TGF-
-binding
protein. The latency-associated protein inhibits binding of TGF-
to
its receptor. Dissociation of the potentially active molecule from the
complex may be accomplished by a number of environmental triggers,
including heat, shear force, pH extremes, and proteolysis
(67). The concepts of latency and activation are important
and often overlooked in studies of TGF-
production, secretion, and
effects (68). In addition, the local availability of
TGF-
is not usually taken into consideration. It binds to the ECM
(perhaps facilitated by the latent TGF-
-binding protein) with a
KD of ~10
8 M, while the
KD for the receptor is at least an order of
magnitude lower (22). These affinity differences permit
the ECM to function as a reservoir, releasing the growth factor when
the local concentration falls below the ECM KD
while maintaining an ambient level sufficient to bind to the cell
receptors. This modulation of local concentration is a critical
determinant of the effects of TGF-
in a given system.
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TGF--family ligands bind to a corresponding family of receptors that
is comprised of seven type I receptors (T
R-I) and five type II
receptors (T
R-II) (5). T
R-I and T
R-II may form a variety of heterodimers; several of these have been described in renal
cells (55). There are some unique aspects of
TGF-
-family signal transduction. First, whereas most growth factor
receptors are tyrosine kinases, the TGF-
-family receptors function
as membrane-bound serine/threonine kinases. Second, most receptors
signal by activating a cascade of second messengers that transmit
signals toward the nucleus, culminating in the activation of a
transcription factor; or, in the case of the steroid hormone receptor
family, the ligand binds to a cytoplasmic receptor that itself serves
as a transcription factor. The TGF-
-family receptors are unique in
that they are integral membrane receptors which bind to and activate
proteins that translocate to the nucleus to regulate transcription
rather than initiate a cascade. Viewed in terms of function and
complexity, these attributes suggest that the mechanism of action of
this family of receptors is an evolutionary intermediate between those of the nuclear hormone receptors and the receptor tyrosine kinases.
The proteins that are activated by the TGF--family receptors are
called "Smad" proteins. The Smads were originally described simultaneously by the fly and worm scientific communities. In Drosophila melanogaster, a gene product was determined to
play a role in embryological patterning regulated by a BMP homologue called decapentaplegic and was termed "MAD" (for "mothers against decapentaplegic") (91). Researchers investigating the
developmental genetics of Caenorhabditis elegans identified
a series of proteins that, when mutated, produced an identical, small
phenotype in the worms (indicating a common effector pathway for these
molecules). They termed this family the "Sma" proteins
(84). Eventually, a consensus name, Smad, was agreed on.
The Smads have a general structure of two MAD homology (MH) domains
connected by a linker region (Fig. 2).
The protein-amino acid sequence includes a number of serines and
threonines that represent potential phosphoacceptor sites. On ligand
binding, TR-II transphosphorylates T
R-I (Fig.
3). Two receptor heterodimers combine to
form a tetramer that binds to a subfamily of Smads termed the R-Smads,
which are receptor activated and also pathway restricted (Smad2 and
Smad3 for TGF-
and activin; Smad1, -5, and -8 for the BMPs)
(60). Smad2 and Smad3 are recruited to the cell membrane
receptor through their affinity for the Smad anchor for receptor
activation, a protein that has a binding domain specific for
TGF-
-family receptors (100). The quiescent R-Smads maintain a hairpin configuration until becoming phosphorylated at a
COOH-terminal SSXS motif, whereupon they spring open and become active.
The activated R-Smads form heteromultimers with a second type of Smad,
the common-pathway Smad called Smad4. This complex is translocated to
the nucleus, where it participates in transcriptional regulation
(76). Initially, it was uncertain whether Smads bound
directly to DNA or attached through an intermediary protein complex
(14, 113). Subsequently, however, a Smad-binding element,
including the sequence CAGA, has been characterized (43, 110). Nonetheless, in most cases transcriptional activation, even when demonstrably Smad dependent, requires the binding of additional transcription factors. Transcriptional cooperation has been
demonstrated with proteins such as AP-1 transcription factors
(113), Fast-1 (14), Fast-2 (50),
TFE3 (35), and Sp1 (18, 51, 112). R-Smads and
Smad4 have also been shown to interact with the binding protein for
cAMP-response element binding protein/p300 coactivators (92,
104). Inhibiting factors include TRIP-1 (16), SnoN
(96), Ski (56), and SNIP (46).
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A third category of Smad proteins, the inhibitory Smads (I-Smads),
includes Smad6 (38) and Smad7 (30, 73), which
have been identified in the kidney (101). The I-Smads are
able to bind to TR-I but lack critical phosphoacceptor sites and
therefore prevent phosphorylation of R-Smads. In addition, Smad6 has
been shown to inhibit the binding of Smad4 with R-Smads, decreasing signal in that way as well (29). Smad7 expression is
stimulated by TGF-
in an apparent negative-feedback loop
(69).
The definition of this pathway, and of its unique attributes described
above, has represented a major advance in our understanding of how
TGF--family ligands and their receptors function to transmit signals
into the cell. A caveat regarding this progress is that it was
accomplished primarily utilizing ectopic molecular expression systems
and/or transformed cell lines. Thus much of the initial data focused on
the role of Smads in regulating developmentally expressed genes or cell
proliferation and differentiation in cancer. The first human Smad
mutations were identified in colon (98), pancreatic
(26), and lung (70) cancers, and many more
have been described. However, transformed cells may not have a full complement of signal-regulating proteins. In addition, when signaling proteins are overexpressed in cells, the requirements for specific activation steps and specific subcellular localization, as well as the
potential need for interaction with additional proteins and signaling
pathways, may be freed from subtle physiological regulatory constraints
(65). Thus it has been important that these pathways
should be studied for their function in ligand-activated, nontransformed cells.
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TGF-![]() |
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Several reports have indicated that TGF- stimulates mesangial
cell ECM production. In cultured mouse mesangial cells, TGF-
1 stimulates production of types I and -IV collagen and fibronectin (57). In rat mesangial cells, TGF-
1 has been shown to
have variable effects. In one report, it increased proteoglycan
synthesis without any changes in collagen and fibronectin synthesis
(10, 72), while another group described increased
expression of
1(I) collagen and
1(IV)
collagen and fibronectin genes (97). TGF-
1 also
inhibits plasminogen activator production while stimulating plasminogen
activator inhibitor synthesis by normal rat glomeruli (99). In various assays examining cultured human mesangial
cells or isolated perfused kidneys, TGF-
1 stimulates expression of types I, -III, and -IV collagen, laminin, fibronectin, and heparan sulfate proteoglycans (21, 27, 63, 80).
To define more precisely the nature and timing of changes in matrix
turnover that are stimulated by TGF-, our laboratory evaluated human
mesangial cells. TGF-
1 increases expression of mRNA for the ECM
protease matrix metalloproteinase (MMP)-2, which is paralleled by an
increase in its antagonist, tissue inhibitor of metalloproteinases
(TIMP)-2. There is no change in TIMP-1 or membrane-type MMP mRNA
expression, while the level of MMP-1 mRNA is decreased. At the protein
level, TGF-
1 increases types I and -IV collagen in both the
mesangial cell layer and conditioned media. Many of these changes occur
rapidly, with increased expression of collagen mRNAs beginning within
1-4 h of TGF-
1 treatment. In contrast to the mRNA studies,
MMP-2 and TIMP-1 activity showed little change while MMP-1 did decrease
and TIMP-2 was not detected. Together, the net protease activity did
not appear to change significantly, suggesting that, for regulating
collagen turnover in this short-term cellular model, changes in
protease activity are less significant than those in ECM synthesis
(80). In other model systems, the regulation of ECM
degradation by TGF-
may be at least as important as ECM synthesis
(6).
In addition to the rapid changes in mRNA expression, collagen protein
turnover was faster than anticipated. Treatment of near-confluent cells
with cycloheximide to inhibit protein synthesis for only 4 h
virtually eliminated detectable collagens from the cell layers and
conditioned media. While this result could reflect the scorbutic culture conditions (ascorbate, which facilitates the stabilization of
collagen fibrils in a matrix, was omitted from the culture medium
because it also stimulates collagen synthesis), the results suggested
that mesangial cell collagen protein expression in vitro represents a
steady-state phenomenon rather than simply ongoing accumulation of
synthesized protein. Interestingly, cycloheximide did not affect early
TGF-1-induced changes in mRNA expression but reversed increases in
1(I) collagen mRNA at 24 h, suggesting that early
changes in expression represent direct effects whereas later changes
are mediated by the synthesis of additional proteins. In contrast,
1(IV) collagen mRNA expression did not require
intermediate protein synthesis at any time point but was superinduced
by cycloheximide treatment. These data indicate that, in human
mesangial cells, early changes in net collagen accumulation are
regulated primarily at the level of protein synthesis rather than
degradation and that the mechanisms of type I collagen and type IV
collagen mRNA expression differ significantly (80).
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SMAD SIGNALING IN MESANGIAL CELL ECM ACCUMULATION |
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These data suggested that the most appropriate avenue for the
investigation of immediate profibrotic cellular events in
TGF--stimulated mesangial cells is the examination of ECM synthesis.
Toward this goal, we determined whether Smad activity could be linked
to mesangial cell collagen expression. Mesangial cells express at least
Smad1, -2, -3, -4, and -7. Stimulation of human mesangial cells with TGF-
1 induces phosphorylation of Smad2 and Smad3, beginning within 5 min of exposure. Phosphorylation peaks at 30 min but remains present
for as long as 24 h (79, 83). The phosphorylation event is paralleled by association among Smad2, -3, and -4. Phosphorylation and association are followed within minutes by
increased nuclear localization of this complex. Activity of the
TGF-
/Smad-responsive p3TP-Lux promoter-reporter construct is
stimulated by TGF-
1 treatment. These data are consistent with the
model that ligand-stimulated Smad activation in mesangial cells leads
to transcriptional activity in the nucleus, in parallel with previous
results derived from the study of transformed cells or overexpressed
Smads. The
1(I) collagen and
2(I)
collagen promoters are also activated (31, 79); and
activation of a collagen promoter-luciferase reporter construct is
inhibited by Smad3A, a mutated Smad3 expression construct that lacks
critical COOH-terminal serine phosphoacceptor sites and functions as a
dominant-negative mutant in this assay (79). Together,
these results demonstrate that the Smad pathway is present and
functional in mesangial cells and that it can mediate
TGF-
-stimulated collagen I expression. Further support for typical
Smad pathway interactions regulating collagen production is provided by
the finding of other groups that Smad7 decreases TGF-
-stimulated mesangial cell collagen production (13, 54). Another way
in which Smad7 signaling can affect the sclerosing process is by inducing podocyte apoptosis (85).
It is noteworthy that, while the dominant-negative mutant Smad3A blocks
TGF- stimulation of COL1A2 promoter-luciferase reporter activity,
simply expressing either wild-type Smad3 or Smad3A leads to a large
increase (15- and 8-fold, respectively) in basal responses (79). Thus, although the Smad3A construct does not
transduce the receptor-activated signal, its overexpression appears to
at least partly bypass the requirement for activation. This observation illustrates the concern raised previously about the impact of overexpressing specific proteins on the geometry or the stoichiometry of the cellular signaling response.
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CROSS TALK BETWEEN SMAD SIGNALING AND MAP KINASE PATHWAYS |
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Thus the interpretation of these studies can be complicated by
technical as well as biological factors. Moreover, investigators examining the response of different cells to an identical stimulus have
reported varied and contradictory findings. This outcome has been
attributed to myriad differences in experimental conditions, including
the culture media used, the question of whether the cells are
transformed, the timing and conditions of treatment, etc. However, it
is increasingly accepted that such differences may be real and may
define tissue specificity in an organism. For example, an endothelial
cell will respond differently from a smooth muscle cell, even though
the basic signaling pathways in the two cell types are similar. The
likely source of this heterogeneity is cross talk among different
signal transduction pathways that are present and active to varying
degrees in different cells (86). While the paradigm of
Smad activation described above is likely to exist in most cells,
interaction of Smads with other signals may significantly alter their
function. For example, TGF-1 may stimulate a variety of kinases in
mesangial cells, including protein kinase A (103) and
casein kinase II (111). In rat mesangial cells, TGF-
has been shown to activate ERK and p38 MAP kinase (15,
36). Activation of p38 has been implicated in
TGF-
1-stimulated
1(I) collagen mRNA expression
(15), whereas ERK has been associated with fibronectin
accumulation (39). In human mesangial cell studies from
our laboratory, TGF-
1 stimulates phosphorylation of both the ERK-
and JNK-MAP kinase pathways, but not p38 (31). Biochemical
inhibition of ERK reduces TGF-
1-stimulated human mesangial cell
collagen mRNA expression. Moreover, a dominant-negative ERK construct,
but not dominant-negative inhibition of JNK activation, decreases
activation of the TGF-
-specific p3TP-Lux construct as well as a
collagen promoter-luciferase reporter construct (31). These results indicate that the ERK-MAP kinase pathway enhances or
amplifies Smad-mediated mesangial cell responses.
The interaction of ERK with TGF- signaling in mesangial cells is
under investigation. Our preliminary data suggest that ERK enhances
Smad phosphorylation (32). This finding may contribute further to the controversy in the literature regarding the effect of
ERK on Smad activity. Initially, it was felt that ERK activation inhibited Smad signaling (48). More recent studies have
supported both the enhancing (20) and inhibitory
(49) effects of ERK on Smad activation. Inhibiting ERK
decreases Smad-mediated transcriptional activity (31, 32).
These differences could reflect the developmental origin of the tissue
under study, the nature and intensity of the stimulating and inhibitory
signals, the question of whether endogenous or ectopically expressed
proteins were studied, or the specific downstream target of Smads that
is being evaluated. In renal tubular epithelial cells, TGF-
stimulates epithelial-to-mesenchymal transdifferentiation (EMT), a
pivotal event in some models of fibrogenesis (107) (see
below). EMT is inhibited by stimuli of ERK activity (106)
or by mediators that have been associated with ERK activation
(17). The role of ERK in antagonizing the effects of
TGF-
in renal tubular EMT remains to be fully established.
The non-Smad signaling pathways that are activated after TGF-
stimulation have been reviewed recently (77). Although
they clearly play a role in regulating a number of processes in
addition to fibrogenesis (7), the mechanisms by which the
TGF-
receptor mediates these alternative pathways are not well
understood. This is an important area for further investigation.
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INTERACTIONS IN TRANSCRIPTIONAL REGULATION |
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Another potential site of interaction between Smads and other
factors is in the nucleus. As described above, Smad activity likely
requires other transcription factors, including an interaction with Sp1
that has been described in several systems (18, 51, 112).
In human mesangial cells, TGF-1-induced collagen mRNA expression is
inhibited by mithramycin, a blocker of Sp1 DNA binding, but not by
curcumin, which inhibits AP-1 transcriptional activity. TGF-
1
stimulates interaction of Smad3 and Sp1, and the resulting complex
binds to promoter sequences in the COL1A2 gene. Deletion from the promoter of GC boxes that bind to Sp1, or mutation of the CAGA
sequence in the Smad-binding element (SBE), abrogates promoter
activation by TGF-
1. Additional studies showed that the
transcriptional activity of the Sp1 transactivation domain B
was not induced directly by TGF-
1 but instead that this domain became responsive when Smad3 was coexpressed. Thus Smad3 activity is
critical to the response, but Sp1 plays a key role in supporting that
response (81).
Further insight into these events is provided by elegant studies of
laminin-1 gene regulation by Bomsztyk and colleagues (33, 45). The LAMC1 promoter contains a
highly conserved transcriptional element, termed bcn-1. With the use of
a yeast one-hybrid approach, the TFE3 transcription factor was cloned
from a rat mesangial cell cDNA library, indicating that this basic
helix-loop-helix/leucine zipper transcription factor binds
to bcn-1. Stimulation of bcn-1 by TGF-
to activate the
LAMC1 promoter was enhanced by overexpression of Smad3 and
was dependent on the Smad-binding element in the LAMC1
promoter (45). In addition, a similar strategy identified binding of the gut-enriched Kruppel-like factor (GKLF) to bcn-1. GKLF
activity was dependent on synergy with Sp1 (33). Although this second study did not address the role of TGF-
, the involvement of Sp1 in these events and the responsiveness of GKLFs to
TGF-
-family ligands in other experimental systems (1)
suggest that multiple transcription factors, binding to multiple sites,
cooperate to induce ECM protein gene expression in response to TGF-
stimulation. Additional protein-protein interactions at the level of
gene transcription include those of Smad with p300, shown in several
systems (23, 104), and with estrogen receptor
(61).
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EFFECTS OF TGF-![]() |
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The paradigm of TGF- signaling through Smads involves a
transcriptional mechanism of action and, by extension, delayed
responses. However, other responses may be more immediate in some
circumstances, suggesting nontranscriptional actions. For example,
TGF-
1 rapidly stimulates Ca2+ influx, without promoting
Ca2+ release, in SV-40-transformed murine mesangial cells.
This response is inhibited by pharmacological inhibitors of
inositol-1,4,5-trisphosphate (IP3) receptors and by an
antibody to the type III IP3 receptor. Whereas untreated
mesangial cells had numerous, spike-like projections on their cell
surface, TGF-
1 treatment reduced these projections in a
Ca2+-dependent manner within 15 min (62).
In preliminary studies, we have found that treatment of human mesangial
cells with TGF-1 not only stimulates cytoskeletal rearrangement
but also increases incorporation of
-smooth muscle actin
(
-SMA) into stress fibers. Our evidence suggests that these cytoskeletal changes could play a role in collagen expression (Hubchak
and Schnaper, unpublished observations). One mechanism for this
role could relate to a theory of fibrogenesis that has gained
increasing attention: that fibrosis requires resident tissue cells to
differentiate into fibroblasts. In atherosclerosis, this has been
characterized as vascular smooth muscle cells assuming a
"myofibroblastoid phenotype." In mesangial cells, altered collagen expression after TGF-
treatment has been associated with increased expression of
-SMA (37). The phenomenon has been more
fully described in the tubular epithelium, where the tubular cell
transdifferentiates from an epithelial cell phenotype to a
fibroblastoid cell that produces and secretes ECM (107),
in a process that also is associated with increased
-SMA
incorporation into stress fibers (107).
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IMPLICATIONS OF TGF-![]() |
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Taken together, the data presented here suggest that TGF-
stimulates several pathways in mesangial cells (Fig.
4). In addition to the Smad pathway,
Ca2+ influx and MAP kinases are activated; there may be an
as yet undetermined hierarchy to these signals. These pathways in turn synergize, perhaps through effects on each other or through parallel tracks into the nucleus, where a variety of transcription factors interact to modulate the transcription of ECM genes. Other events in
the glomerulus that may be mediated by Smads, such as endothelial nitric oxide synthase gene expression (108) or cell
apoptosis (41, 78, 85), also could affect
glomerular function and sclerosis.
|
While we have emphasized transcriptional effects of these pathways,
posttranslational effects such as alterations in the activity of ECM
proteases also could modulate the accumulation of ECM. For example,
TGF- has been reported to decrease (74) or increase (58) the expression or activity of the MMPs that degrade
ECM or the tissue inhibitors of MMPs that slow matrix degradation. Cytochalasin D, a pharmacological agent that disrupts the cytoskeleton, stimulates the activation of MMP-2, increasing collagen degradation (2). Thus the effects of TGF-
on other biological
events that affect ECM turnover, and potential nontranscriptional
mechanisms of TGF-
signaling, are areas of importance that presently
are under-studied.
An even more important area of potential investigation is the role of
these newly defined pathways in fibrogenesis in vivo. It is clear that
increasing TGF- expression either locally or systemically
(66) causes glomerular or renal fibrosis. Inhibition of
TGF-
binding to its receptor can lessen the degree of experimental renal fibrosis (42). Hong and colleagues (34)
have associated the TGF-
/Smad signaling pathway with an animal model
of diabetic renal disease. However, studies of the effects of
interrupting Smad signaling on renal fibrogenesis have not been
performed. The lack of pharmacological inhibitors of Smad signaling has
prevented all but the most rudimentary studies of how Smad signaling
might be regulated in vivo. A possible approach might involve new
techniques of local gene expression (71, 82) to increase
intracellular levels of I-Smads. Significant technical advances will be
required for such approaches to be feasible. Thus our expanded
understanding of this field over the past several years offers great
promise but one that requires considerable additional investment before it will reach fruition.
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NOTE ADDED IN PROOF |
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Further evidence of a role for inhibitory Smads in glomerular
disease is found in an article by Schiffer and colleagues (Schiffer M,
Schiffer LE, Gupta A, Shaw AS, Roberts ISD, Mundel P, and
Böttinger EP. Inhibitory Smads and TGF- signaling in
glomerular cells. J Am Soc Nephrol 13: 2657-2666,
2002), reporting altered podocyte I-Smad expression in human disease.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-49362 and a grant to Dr. A.-C. Poncelet from the National Kidney Foundation of Illinois.
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FOOTNOTES |
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Address for correspondence: H. W. Schnaper, Pediatrics W-140, 303 E. Chicago Ave., Chicago, IL 60611-3008 (E-mail: schnaper{at}northwestern.edu).
10.1152/ajprenal.00300.2002
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