Division of Nephrology and Hypertension, Harbor-UCLA Medical Center and University of California Los Angeles, Torrance, California 90509
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ABSTRACT |
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Glomerular
proteinuria is a risk factor for progression of chronic renal failure
and contributes to renal interstitial fibrosis. In experimental
diabetic glomerular sclerosis, there is translocation of
high-molecular-weight growth factors, namely, hepatocyte growth factor
(HGF) and transforming growth factor (TGF)-, from plasma into
tubular fluid, both of which act on tubular cells through apical
membrane receptors. In the present studies, the hypothesis is examined
that ultrafiltered HGF and TGF-
induce increased expression of
extracellular matrix (ECM) proteins directly in tubular cells, or
induce increased expression of cytokines that may act on interstitial
myofibroblasts. Incubation of cultured tubular cells with recombinant
human (rh) TGF-
modestly raises expression of collagen type III, but
rhHGF dose dependently blocks expression of this ECM protein. Both
growth factors raise fibronectin expression up to fourfold and increase
expression of platelet-derived growth factor (PDGF)-BB up to sixfold,
but not of fibroblast growth factor-2. Pooled, diluted glomerular
ultrafiltrate that had been collected by nephron micropuncture from
rats with diabetic nephropathy (24-30 wk) also raises expression
of fibronectin as well as PDGF-BB in proximal tubular cells. In the
presence of neutralizing antibodies that block actions of HGF and
TGF-
, diabetic rat glomerular ultrafiltrate fails to increase
tubular cell PDGF-BB expression. In NRK-49F renal interstitial
myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen
type III but not type I or fibronectin. The findings provide evidence
for ultrafiltered HGF and TGF-
to contribute to interstitial
accumulation of ECM proteins by direct effects on tubular cells as well
as indirect mechanisms, via PDGF-BB and its action on myofibroblasts.
These events may be important mechanisms of proteinuria-induced renal
interstitial fibrosis and accelerated progression of chronic renal
failure in diabetic nephropathy and perhaps other proteinuric
glomerular diseases.
collagen; fibronectin; renal interstitial fibrosis
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INTRODUCTION |
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GLOMERULAR PROTEINURIA IS a risk factor for progression of renal failure and is associated with progressive interstitial fibrosis (3, 5, 7, 10, 11, 16, 19-22). This relationship between glomerular protein ultrafiltration and interstitial fibrosis is universal and not limited to certain glomerular diseases. In fact, this rule applies to immunological as well as nonimmunological, primary, and secondary glomerular diseases as well as to diabetic nephropathy (4-6).
Previous studies from this laboratory have indicated that in the
adriamycin-induced nephrotic syndrome and in streptozotocin-induced diabetic nephropathy in rats, glomerular ultrafiltration of proteins leads to translocation of high-molecular-weight growth factors into
tubular fluid, including insulin-like growth factor (IGF)-I, transforming growth factor (TGF)-, and hepatocyte growth factor (HGF) (14, 28, 29). These growth factors become activated in tubular
fluid and act on tubular cells through specific IGF-I, TGF-
, and HGF
receptors, respectively, that are expressed in apical membranes
(1, 12, 14, 28, 29). Ultrafiltered TGF-
and HGF "activate"
tubular cells and raise the expression and basolateral secretion of
monocyte chemoattractant protein (MCP)-1 and regulated on activation,
normal T cell expressed and secreted (RANTES) (27). These C-C
chemokines attract and activate macrophages, and macrophage-derived
TGF-
increases the expression of extracellular matrix proteins in
interstitial myofibroblasts.
Because of the presence of ultrafiltered growth factors, diabetic rat proximal tubular fluid may "transform" tubular cells, i.e., may induce increased expression of extracellular matrix proteins in tubular cells. Growth factors that are present in glomerular ultrafiltrate may induce increased expression and basolateral secretion of cytokines in tubular cells that can directly interact with interstitial myofibroblasts without acting through macrophages as intermediaries.
In the present studies, the hypothesis was tested that HGF and TGF-
in glomerular ultrafiltrate from rats with diabetic nephropathy act
directly on urinary space-lining epithelial cells of the nephron causing increased expression of interstitial extracellular matrix proteins such as collagen (col)
2I, col
1III, and fibronectin. Moreover, the interaction of
tubular fluid growth factors may increase the expression of cytokines
such as platelet-derived growth factor (PDGF) and fibroblast growth
factor (FGF)-2 that may stimulate interstitial fibroblasts to express
increased amounts of interstitial matrix proteins.
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METHODS |
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To test this hypothesis, experiments were performed in cultured tubular
cells that were exposed to glomerular ultrafiltrate that was collected
extensively from rats with diabetic nephropathy. Glomerular
ultrafiltrate from rats with diabetic nephropathy (24-30 wk) but
not from control rats contains active HGF and TGF- (26, 28).
In Vivo Studies
Early proximal tubular fluid was collected from Spraque-Dawley rats at 24-30 wk after induction of diabetes with streptozotocin (85 mg/kg). Animals were given subcutaneous insulin to maintain blood glucose at 300-350 mg/dl. The micropuncture techniques to collect intensively glomerular ultrafiltrate from diabetic and control rats have been described previously (14). Glomerular ultrafiltrate from rats with diabetic nephropathy at 24-30 wk of diabetes contains HGF as demonstrated previously by Western blot analysis in this laboratory, and glomerular ultrafiltrate from normal control rats does not contain HGF at levels recognized by this method (26-28). Levels of total and active TGF-In Vitro Studies
Cell cultures.
In vitro studies of effects of proximal tubular fluid, recombinant
human (rh) HGF, and rhTGF- were performed in cultured cells
originated from mouse proximal tubules and medullary collecting ducts.
Mouse proximal tubular cells (mPTC) had been obtained as a kind gift
from Dr. Carolyn Kelly (Univ. of California San Diego). These cells
were originally outgrown from proximal tubule S3 segments and immortalized by transfection with the simian virus 40 T antigen (13). Mouse inner medullary collecting duct cells (mIMCD-3) and NRK-49F
cells, which are rat kidney-derived myofibroblasts, were obtained from
a commercial source (ATCC, Rockville, MD). These latter cells express
-smooth muscle actin as tested in this laboratory. All cells were
grown in DMEM/Ham's F-12 containing normal culture medium glucose
levels (100 mg/dl) and supplemented with 10% FCS.
Effect of diabetic rat glomerular ultrafiltrate and recombinant
growth factors on the expression of collagen type I and III and
fibronectin in proximal tubular and collecting duct cells.
Proximal tubular cells were grown in 96-well plates to ~80%
confluence and then growth arrested by incubation with serum-free medium containing BSA (25 µg/ml). Cells were then exposed for 24 h to
serum-free medium (control) or medium containing pooled, diluted (1:5)
proximal tubular fluid (25 µl/well) that had been collected by
micropuncture from rats with diabetic nephropathy (n = 4). In
separate experiments, proximal tubular cells were also incubated in
24-well plates with serum-free medium (control) or medium containing
either rhHGF (1 nM, R&D Systems, Minneapolis, MN) or rhTGF-1 (1 nM,
R&D Systems) (n = 6 each). Media were removed, and RNA was
extracted using the RNA-Stat-60 reagent and the method recommended by
the manufacturer (Tel-Test, Friendswood, TX).
Effect of diabetic rat glomerular ultrafiltrate and rhHGF and
rhTGF- on tubular cell expression of cytokine growth
factors (PDGF-B and FGF-2).
Previous studies from this laboratory had shown that HGF and TGF-
,
which are both present in tubular fluid in rats with glomerular proteinuria, activate tubular cells through apical membrane receptors causing basolateral secretion of the two C-C chemokines MCP-1 and
RANTES (manuscript in press). These chemokines cause peritubular attraction and activation of macrophages that express growth factors, primarily TGF-
, which in turn raise the expression of extracellular matrix proteins by interstitial fibroblasts. However, ultrafiltered HGF
and TGF-
may also induce increased expression of cytokine growth
factors in tubular cells that may then directly interact with
interstitial fibroblasts raising the expression of extracellular matrix
proteins without macrophages acting as intermediaries.
Effect of rhPDGF-B on expression of extracellular matrix proteins
in cultured rat renal myofibroblasts.
PDGF-B, which is derived from tubular cells and augmented by HGF- and
TGF--containing diabetic rat tubular fluid, may act on interstitial
myofibroblasts and induce increased expression of extracellular matrix
proteins by these latter cells.
Statistical Analysis
PCR-derived mRNA levels are expressed as ratio over GAPDH mRNA. Data are means ± SE. Comparisons were made by ANOVA followed by Student-Newman-Keuls multicomparison tests. ![]() |
RESULTS |
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At the time of early proximal tubular fluid collection by nephron micropuncture (24-30 wk after induction of diabetes), renal histology was examined qualitatively by light microscopy of periodic acid-Schiff-stained slides. Glomeruli were minimally abnormal and showed mild mesangial widening. The renal interstitium was not expanded. However, rats were proteinuric, and the total urinary protein excretion was 145 ± 19 µg/min as measured in bladder urine that was collected during the micropuncture procedures.
Glomerular Ultrafiltrate From Diabetic Rats and HGF and
TGF- Raise the Expression of Extracellular Matrix
Proteins in Tubular Cells
Col 1III is expressed in proximal tubular cells.
Incubation of the cells with TGF-
(2 nM) moderately increases col
1III mRNA levels by ~40% (Fig.
1A). In contrast, incubation with
rhHGF does not increase col
1III mRNA levels, and high
concentrations of this growth factor (which likely exceed the in vivo
levels of HGF in glomerular ultrafiltrate) lower col
1III expression in proximal tubular cells (Fig.
1B).
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Both proximal tubular as well as mIMCD-3 cells express fibronectin
under control conditions, and interstitial accumulation of fibronectin
contributes to interstitial fibrosis. Both growth factors, HGF and
TGF-, which are present in glomerular ultrafiltrate from rats with
diabetic nephropathy but not from control animals, increase the
expression of this extracellular matrix protein directly in tubular
cells (Fig. 2). At equimolar
concentrations, the effects of TGF-
on fibronectin expression are
more potent compared with HGF. In proximal tubular cells, incubation
with HGF or TGF-
(2 nM) for 48 h increases fibronectin mRNA levels
about two- and threefold, respectively (Fig. 2). Incubation of the
cells with rhHGF at 0.2 or 2 nM for only 24 h fails to increase
fibronectin mRNA levels in proximal tubular cells, and 4 nM HGF raises
fibronectin within 24 h of incubation to 165 ± 9% of control values
(P < 0.05). This suggests that the action of HGF in diabetic
rat tubular fluid on expression of fibronectin is relatively weak
compared with TGF-
. Nevertheless, direct actions of ultrafiltered
HGF and TGF-
contribute to increased expression of ECM proteins,
specifically collagen type III and fibronectin, in proximal tubular
cells.
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In mIMCD-3 cells, both HGF as well as TGF- raise the expression of
fibronectin within 24 h of incubation up to 3.5-fold (Fig. 3). Although these cells seem to react more
sensitively to HGF compared with proximal tubular cells, the effect of
equimolar TGF-
on fibronectin expression in mIMCD-3 cells appears to
be greater compared with rhHGF (Fig. 3).
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Incubation of proximal tubular cells with pooled diabetic rat
glomerular ultrafiltrate also increases the expression of fibronectin (Fig. 4). Although the increase appears to
be moderate in magnitude, on average ~51%, it should be taken into
account that the tubular fluid was fivefold diluted with serum-free
medium. Given that in vivo accumulation of extracellular matrix in
renal interstitial fibrosis is a very slow but progressive process,
this rise in fibronectin expression, although moderate, is likely to
make important contributions.
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HGF, TGF-, and Diabetic Rat Glomerular Ultrafiltrate
Increase the Expression of PDGF-B But Not of FGF-2 in Tubular
Cells
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In mIMCD-3 cells, the effect of each of the two growth factors appears
weaker compared with proximal tubular cells. In mIMCD-3 cells, 1 nM HGF
does not significantly increase PDGF-B mRNA, and equimolar TGF-
raises PDGF-B mRNA levels 3.4 ± 0.3-fold (P < 0.05).
In both proximal tubular as well as mIMCD-3 cells, FGF-2 mRNA is not
detectable in the baseline state with the RT-PCR method used.
Incubation with either HGF (1 nM) or TGF- (1 nM) does not increase
FGF-2 mRNA, at least not to the extent measurable with the current method.
Effects of PDGF-B on the Expression of Extracellular Matrix Proteins in Rat Renal Interstitial Myofibroblasts
In vivo, tubular cell-derived PDGF-B may interact with interstitial fibroblasts. In the kidney, interstitial fibroblasts are believed to be the major source for extracellular matrix proteins that accumulate in renal interstitial fibrosis. Hence, PDGF-B may be an important tubule-derived mediator of proteinuria-induced interstitial fibrosis.In the present studies, NRK-49F rat renal fibroblasts were incubated
with rhPDGF-B (1 nM) or, for comparison, with TGF-1 (400 pM). As
shown in Fig. 7, incubation of fibroblasts
with PDGF-BB failed to increase col
2I or fibronectin
mRNA (Fig. 7, A and C) but increased col
1III mRNA levels significantly (P < 0.05, Fig.
7B). In contrast, TGF-
, which may be primarily derived from macrophages in vivo, increased the expression of each of the three extracellular matrix proteins in rat renal myofibroblasts about 2.5- to
4-fold (Fig. 7).
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DISCUSSION |
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Clinical trials and clinicopathological studies have indicated that there are correlations between the degree of glomerular proteinuria, interstitial fibrosis, and the rate of progression of chronic renal failure (2, 5, 20, 22). These relationships have been shown to occur in diabetic nephropathy as well as in other (primary or secondary) glomerular diseases.
Glomerular proteinuria in experimental diabetic nephropathy causes
glomerular ultrafiltration of HGF and TGF- into tubular fluid (25,
26, 28). Both growth factors interact with their specific receptors
that are present in apical membranes in various tubular segments (12,
25, 26). Ultrafiltered HGF and TGF-
may each act on tubular cells
separately and independently, or may act synergistically. Synergistic
interactions of TGF-
and HGF signaling pathways have recently been
described (9).
There are essentially three types of pathways through which
ultrafiltered HGF and TGF- may contribute to the accumulation of
extracellular matrix proteins in the peritubular interstitium and,
hence, to progressive interstitial fibrosis. First, ultrafiltered HGF
and TGF-
induce increased extracellular matrix production directly
in tubular cells as shown in the present studies. Indeed, as shown in
Fig. 4, early proximal tubular fluid obtained from rats with diabetic
nephropathy by micropuncture which contains the two growth factors
raises fibronectin expression in tubular cells. Equimolar comparisons
between the effects of TGF-
and HGF on tubular cell fibronectin
expression indicate that the effects of ultrafiltered TGF-
are
greater in this respect than those of HGF (Figs. 2 and 3). TGF-
increases collagen type III mRNA levels (Fig. 1A), but HGF
fails to increase the expression of this extracellular matrix protein
in proximal tubular cells (Fig. 1B). At high concentrations,
HGF actually reduces the expression of collagen type III. Although
actual levels of HGF in proximal tubular fluid from rats with diabetic
nephropathy are not known since the presence of this growth factor had
been demonstrated with a nonquantitative method (Western blot
analysis), it is fair to estimate that levels are most likely lower
than is required for reducing collagen type III expression. To this
end, it is noteworthy that transgenic mice overexpressing HGF develop
renal fibrosis (23). Hence, TGF-
and perhaps HGF, which are both present in tubular fluid in diabetic nephropathy (and likely in other
nephrotic glomerular diseases), may contribute to interstitial fibrosis
by directly raising expression of certain extracellular matrix proteins
such as collagen type III and fibronectin in tubular cells.
Second, ultrafiltered HGF and TGF- increase tubular cell expression
of cytokine growth factors, specifically, PDGF-B as shown in the
present studies. Although it is difficult to quantitatively translate
in vitro findings into in vivo pathobiological events, it appears from
respective experimental findings in the current studies that this
indirect pathway involving tubular cell PDGF-B may contribute only
moderately, since only one out of three extracellular matrix proteins,
namely, collagen type III, increased upon incubation of myofibroblasts
with PDGF-BB. However, this latter pathway is macrophage independent.
Tang et al. (24) demonstrated in vivo that actions of PDGF-BB on renal
fibroblasts contribute to the development of interstitial fibrosis, and
several other investigators (8, 15, 17, 18) demonstrated that PDGF
raises extracellular matrix expression and activates renal and nonrenal fibroblasts.
Third, ultrafiltered HGF and TGF- interact with apical tubular cell
receptors and raise the basolateral secretion of MCP-1 and RANTES and
perhaps other chemokines as recently shown in this laboratory
(manuscript in press; 28). These C-C chemokines attract macrophages
that secrete TGF-
and may, in fact, be the dominant source for renal
interstitial TGF-
activity (10). Even though diabetic nephropathy is
generally not perceived as an inflammatory disease, a renal
interstitial macrophage infiltrate does occur, and its onset precedes
measurable interstitial fibrosis (5). Macrophage-derived TGF-
can
act on interstitial myofibroblasts inducing increased production of
extracellular matrix proteins. Experimental evidence supporting this
indirect pathway has been previously demonstrated in this laboratory
(manuscript in press; 27).
Findings from this study point toward the importance of tubular
epithelial cells as the initial targets of glomerular proteinuria and
ultrafiltered HGF and TGF- as the signals that initiate cell-cell interactions that contribute to interstitial fibrosis. Current therapeutic strategies to reduce the effects of glomerular proteinuria on tubulointerstitial injury and progression of renal failure aim at
reducing the rate of glomerular protein ultrafiltration with
antihypertensives, specifically with angiotensin-converting enzyme
inhibitors. However, interruption of activation of tubular cells by
ultrafiltered proteins, specifically high-molecular-weight growth
factors (TGF-
, HGF), could open additional avenues of treatment and prevention.
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ACKNOWLEDGEMENTS |
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This work was supported by Juvenile Diabetes Foundation Grants 196050 and 1-1998-350. S.-N. Wang was supported by a grant from the National Kidney Foundation of Southern California.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. Hirschberg, Div. of Nephrology and Hypertension, Harbor-UCLA Medical Center, Box 406, 1000 West Carson St., Torrance, CA 90509 (E-mail: rhirschberg{at}rei.edu).
Received 5 August 1999; accepted in final form 2 November 1999.
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