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*Division of Nephrology and Immunology, University of Aachen, Aachen, Germany; Ludwig Institute for Cancer Research, Stockholm, Sweden; and German Cancer Research Institute, DKFZ Heidelberg, Germany.
Correspondence to: Dr. Frank Eitner, Klinikum der RWTH Aachen, Medizinische Klinik II (Nephrologie und Immunologie), Pauwelsstr 30, 52074 Aachen, Germany. Phone: 49-241-8089-670; Fax: 49-241-8082-446; E-mail: feitner{at}ukaachen.de
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit and ß-subunit are constitutively expressed in the kidney. Although the -subunit is present in vascular smooth muscle cells and the renal interstitium, the ß-subunit is constitutively expressed in mesangial and parietal glomerular epithelial cells, in vascular smooth muscle cells, and in renal interstitial cells (4). Increased expression of PDGF receptors at sites of renal injury has been documented in a large variety of diseases (4).
A new member of the PDGF family has recently been identified and subsequently termed PDGF-C (7). PDGF-C, like PDGF-A and -B, forms a disulphide-bonded dimer, PDGF-CC. Li et al. (7) identified PDGF-CC as a PDGFR--specific ligand, and Gilbertsson et al. (8) showed that PDGF-CC could activate the beta receptor in a heterodimeric complex. There is no detectable binding or activation to beta receptor homodimers (Gilbertsson et al. (8) and our unpublished data). Transgenic overexpression of PDGF-C in the heart induced a significant proliferation of myocardial interstitial cells in addition to an increase in extracellular matrix production (7). To date, information on PDGF-C in the kidney is limited to the demonstration of abundant PDGF-C transcripts in human kidney (7). In addition, strong PDGF-C mRNA expression was detected in the metanephric mesenchymal aggregates during murine nephrogenesis, suggesting a role for PDGF-C in mesenchymal epithelial conversion as a prelude to tubular development (7). This study is the first to identify PDGF-C as a potent mitogenic stimulus for cultured mesangial cells in vitro. The localization of the cytokine PDGF-C in normal or diseased adult renal tissues as well as its function in vivo are unknown. We therefore analyzed the expression of PDGF-C by immunohistochemistry in renal tissues obtained from healthy normal adult rats and from rats with different renal diseases. Studied renal diseases included rats with immune-mediated mesangioproliferative anti-Thy 1.1 glomerulonephritis, rats with immune-mediated podocyte injury (passive Heymann nephritis [PHN]), rats with toxic podocyte injury (puromycine aminonucleoside nephrosis [PAN]), rats developing a spontaneous glomerulosclerosis (Milan normotensive rats), and obese Zucker rats with hyperlipidemic and type II diabetic renal damage. Although PDGF-B is a known potent mesangial mitogen in vivo, a potential role of PDGF-C in mesangioproliferative glomerulonephritis in vivo is currently unknown. To address whether PDGF-C, which at least partially binds to the same receptors as PDGF-B, uses different pathways than PDGF-B in mediating mesangial cell proliferation in vivo, we also analyzed whether inhibition of PDGF-B (via PDGF-B specific aptamers) influenced the expression of PDGF-C in the anti-Thy 1.1 glomerulonephritis model.
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Materials and Methods |
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Normal Rats.
Eight male Wistar rats (Charles River Wiga GmbH, Sulzfeld, Germany) weighing 140 to 180 g remained untreated and served as healthy control animals.
Mesangioproliferative Anti-Thy 1.1 Nephritis.
Anti-Thy 1.1 nephritis was induced in 16 male Wistar rats (Charles River Wiga GmbH; weighing 160 to 180 g at the start of the experiment) by intravenous injection of 1 mg/kg monoclonal anti-Thy 1.1 antibody (clone OX-7; European Collection of Animal Cell Cultures, Salisbury, UK) as described (9). Animals remained untreated and were sacrificed at days 1, 4, 6, and 85 after induction of the disease (n = 4 at each time point).
Antagonism of PDGF-B after Induction of Anti-Thy 1.1 Glomerulonephritis.
PDGF-C expression was additionally studied in ten rats that were treated with PDGF-B-specific or irrelevant (scrambled) control aptamers as described (9). Anti-Thy-1.1 nephritis was induced in ten male Wistar rats (Charles River Wiga GmbH) as described above. Rats were treated with aptamers from days 3 until sacrifice at day 6 after disease induction. Treatment consisted of twice-daily intravenous bolus injections of the substances dissolved in 400 µl of phosphate-buffered saline (PBS), pH 7.4. Five rats received 0.66 mg/d PDGF-B specific aptamer, and five rats received 0.66 mg/d scrambled aptamer.
Passive Heymann Nephritis.
PHN was induced in four male Sprague-Dawley rats (Charles River Wiga GmbH; weighing 230 to 240 g) by intravenous injection of 0.8 ml of sheep anti-Fx1a antibody per rat (10). Animals remained untreated and were sacrificed at day 8 after induction of the disease.
Puromycine Aminonucleoside Nephrosis.
PAN was induced in two male Sprague-Dawley rats (Charles River Wiga GmbH; weighing 210 to 230 g) by intravenous injection of 150 mg/kg puromycin (Sigma-Aldrich Chemie GmbH, Deisenhofen, Germany) dissolved in normal saline as described (11). Renal tissues were obtained after sacrifice on day 7.
Milan Normotensive Rats.
Two Milan normotensive rats were obtained from the Hannover Medical School, Germany. Renal tissues were obtained after sacrifice at 40 wk of age (12).
Obese Zucker Rats.
Three male obese (fa/fa) Zucker rats were obtained from Charles River Wiga. Renal tissues were obtained after sacrifice at 60 wk of age (13).
Tissues for morphologic evaluation and immunohistochemical analyses were fixed in methyl Carnoy solution, embedded in paraffin, and sectioned. The presence of morphologic features of the different renal diseases was examined in periodic acid-Schiff-stained (PAS-stained) sections. All tissue sections contained a minimum of 50 (usually >100) glomerular cross-sections.
Antibodies
Rabbit antisera directed against PDGF-C were generated as described previously in detail (7). Three different antisera preparations were used in the study: (1) anti-human full-length PDGF-CC, affinity-purified against the core domain of PDGF-CC; (2) anti-human PDGF-CC core domain, affinity-purified against the core domain of PDGF-CC; and (3) anti-mouse PDGF-CC peptide, affinity-purified against the core domain of PDGF-CC. Specificity of these antisera for the detection of PDGF-C has been demonstrated previously by Western blot analyses (7). Further analysis of the specificity of the antisera in immunohistochemical procedures was performed as part of the present study and is detailed below.
Rat renal collecting duct epithelial cells were detected with a rabbit polyclonal antibody directed against rat aquaporin-2 (14). Aquaporin-2 is a vasopressin-regulated water channel expressed exclusively in the renal collecting duct. The antibody was a kind gift of Dr. Mark Knepper, Renal Mechanisms Section, NHLBI, NIH, Bethesda, MD, USA. Additional primary antibodies were identical to those described previously (15,16) and included a murine monoclonal antibody (clone 1A4) to smooth muscle actin, a murine monoclonal antibody (clone PGF-007) to PDGF B-chain, a murine monoclonal IgG antibody (clone ED1) to a cytoplasmic antigen present in monocytes, macrophages, and dendritic cells, affinity-purified polyclonal goat anti-human/bovine type IV collagen IgG preabsorbed with rat erythrocytes, an affinity-purified IgG fraction of a polyclonal rabbit anti-rat fibronectin antibody, and appropriate negative controls as described previously (15,16).
Immunohistochemical Analyses
Immunohistochemical analyses were performed following previously published protocols (17,18). Briefly, methyl Carnoy-fixed, paraffin-embedded tissues were sectioned at 4 µ. Sections were deparaffinized in xylene and rehydrated in graded ethanols. Endogenous peroxidase was blocked by incubation in 3% hydrogen peroxide. The sections were then incubated for 1 h with the primary antibody diluted in PBS containing 1% bovine serum albumin (Sigma). After washes in PBS, the sections were sequentially incubated with biotinylated goat anti-rabbit antibody (Vector, Burlingame, CA), the ABC-Elite reagent (Vector), and finally 3,3'-diaminobenzidine (DAB, Sigma) with nickel chloride enhancement used as the chromogen. Sections were counterstained with methyl green, mounted, and coverslipped. Negative controls consisted of replacement of the primary antiserum with nonimmune rabbit serum. In pilot experiments, we tested the sensitivity and specificity of our procedure. The antibodies were tested at final concentrations between 1 and 15 µg/ml. For the evaluation of the immunoperoxidase stains for -smooth muscle actin, PDGF-B, and PDGF-C, each glomerular area was graded semiquantitatively, and the mean score per biopsy was calculated. Each score mainly reflects changes in the extent rather than intensity of staining and depends on the percentage of the glomerular tuft area showing focally enhanced positive staining: I, 0% to 25%; II, 25% to 50%; III, 50% to 75%; IV, >75%. We have recently described that data obtained using this scoring system are highly correlated with those obtained by computerized morphometry (19).
Cell Cultures/Mesangial Cell Proliferation Assay
The generation of primary rat mesangial cells has been previously described in detail (20). Cells were grown in RPMI 1640 (Sigma) supplemented with 15% fetal calf serum (FCS), 100 U/ml penicillin, and 100 µg/ml streptomycin. Cells were cultured at 37°C in 5% CO2 and were passaged at subconfluency by harvesting with trypsin/ethylenediaminetetraacetic acid. The incorporation of 5-bromo-2'-deoxyuridine (BrdU) into DNA was used as a measurement of mesangial cell proliferation. Mesangial cells (3 x 103 cells/well) were transferred to a 96-well microtiter plate and grown in RPMI 1640 containing 15% FCS until the cells were subconfluent. After incubation for 24 h in RPMI 1640 with 0.5% FCS, cells were stimulated for another 24 h with purified PDGF-CC protein (1 to 50 ng/ml [7]), PDGF-BB protein (1 to 50 ng/ml), PDGF-AA protein (1 to 50 ng/ml) (PDGF-AA and PDGF-BB were kindly provided by J. Hoppe, University of Würzburg, Germany). Cells were labeled with BrdU during the last 4 h of culture according to the manufacturers instructions (Cell proliferation enzyme-linked immunosorbent assay [ELISA], Roche Diagnostics GmbH, Mannheim, Germany). At the end of the incubation period, adherent mesangial cells were washed and denatured. Incorporated BrdU was detected by using a peroxidase-labeled anti-BrdU antibody and a peroxidase color substrate. Finally, the absorbance of the samples was measured in an ELISA reader at 370 nm. Cell proliferation experiments were independently performed four times with duplicate measurements.
Western Blot Analyses
PDGF-C expression was additionally analyzed in protein lysates from cultured primary rat mesangial cells from primary rat smooth muscle cells and from isolated glomerular fractions as described (21). Briefly, cells or isolated glomeruli were homogenized in Triton X-100 lysis buffer (50 mM Hepes, pH 7.5; 150 mM NaCl; 1.5 mM MgCl2; 1 mM ethyleneglycotetraacetic acid; 10% glycerol; 1% Triton X-100; 1 µg/ml aprotinin; 1 µg/ml leupeptin; 1 mM phenylmethylsulfonyl chloride; 0.1 mM sodium orthovanadate) at 4°C. Incubation for 5 min preceded ultrasound treatment (3 x 10 s). The protein concentrations of the resulting solutions were determined using the BCA protein assay (Pierce, Rockford, IL). Forty micrograms of protein were electrophoresed under reducing conditions on a 10% sodium dodecyl sulfate gel and then blotted onto nitrocellulose membranes. The blots were blocked with 2% bovine serum albumin (Sigma) in TTBS (150 mM NaCl; 10 mM Tris, pH 8.0; 0.05% (vol/vol) Tween 20) for 1 h at room temperature and then incubated with the anti-human PDGF-CC core domain antibody diluted in TTBS overnight at 4°C. After several washes in TTBS, the blots were incubated with peroxidase-conjugated horse anti-rabbit IgG antibody (Vector) for 1 h. The blots were visualized with the enhanced chemiluminescence reagent (ECL; Amersham Pharmacia Biotech, Freiburg, Germany).
Statistical Analyses
Data are given as mean ± SD. Statistical significance, defined as P < 0.05, was evaluated by using the t test.
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PDGF-C Acts as a Growth Factor for Mesangial Cells In Vitro
Cultured primary rat mesangial cells were growth arrested and stimulated with PDGF-AA, PDGF-BB, and PDGF-CC. Cell proliferation assays revealed that treatment with purified PDGF-CC protein led to a significant induction of mesangial cell proliferation at PDGF-CC concentrations 10 ng/ml (Figure 4A). Further increase in PDGF-CC concentrations resulted in a dose-dependent increase in mesangial cell proliferation. As expected from numerous previous experiments, both known PDGF-isoforms, PDGF-BB and to a lesser degree PDGF-AA, were capable of inducing dose-dependent mesangial proliferation in similar concentration (Figure 4A).
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-smooth muscle-actin immunostaining scores in PDGF-B aptamer-treated nephritic rats 1.7 ± 0.2 compared with control aptamer-treated nephritis rats 2.3 ± 0.5). Additional in vitro experiments confirmed that the PDGF-B aptamer, although specifically antagonizing the mitogenic activity of PDGF-BB, did not affect the mitogenic effect of PDGF-CC on cultured rat mesangial cells (Figure 4B).
PDGF-C Expression in Experimental Glomerular Diseases Primarily Associated with Podocyte Injuries
We next analyzed the expression of PDGF-C in rat experimental glomerular disease models that were primarily associated with injury to visceral epithelial cells (Table 1).
Animals with toxic podocytic injury (PAN) developed massive proteinuria ranging from 210 to 300 mg/d. Glomeruli remained largely negative for PDGF-C (Figure 5A). Several glomeruli demonstrated a weak granular PDGF-C expression following a mesangial distribution. Visceral epithelial cells, e.g., the primary targets of the experimental disease, remained negative for PDGF-C (Figure 5A). Both, arterial smooth muscle cell and collecting duct PDGF-C expression remained unchanged as compared with normal rats.
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Milan normotensive rats spontaneously develop focal segmental glomerulosclerosis. Visceral epithelial cells had been identified as the primary target of injury in this model (12). The majority of the glomeruli that appeared histologically normal contained no detectable PDGF-C. However, at sites of focal glomerular injury, PDGF-C was localized to visceral epithelial cells (Figure 5C). Glomerular endothelial cells and mesangial cells had no detectable PDGF-C. Another frequent finding was the PDGF-C expression of parietal epithelial cells. PDGF-C expression in vascular smooth muscle cells and in collecting ducts was unchanged.
Obese (fa/fa) Zucker rats develop hyperlipidemia and type IIb diabetes with progressive glomerulosclerosis and tubulointerstitial damage. The four 60-wk-old rats demonstrated significant functional alterations (increased urinary protein excretion, increased plasma creatinine) and significant histologic alterations (focal and segmental glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy) (13). The glomeruli demonstrated a wide range from histologically minimal lesions to segmental sclerosis lesions and finally globally sclerotic glomeruli. Despite the presence of severe glomerular pathology, glomerular PDGF-C expression remained negative in all cases (Figure 5D).
Increase in PDGF-C Expression at Sites of Fibrosing Tubulointerstitial Injury
Most analyzed models of glomerular disease did not develop significant tubulointerstitial pathology because of either the resolution of the injury (anti-Thy 1.1 nephritis) or the early sacrifice after disease induction (day 8 in PAN and PHN). However, 60-wk-old obese diabetic Zucker rats exhibited severe tubulointerstitial disease, including tubular atrophy, tubular microcystic dilation, and tubulointerstitial accumulation of leukocytes and myofibroblasts. At these sites of injury, tubulointerstitial PDGF-C expression was markedly upregulated in all cases analyzed (Figure 6, A and C). PDGF-C was restricted to interstitial cells. The PDGF-C expression pattern of collecting duct epithelial cells remained unchanged compared with normal rats. We were unable to clearly identify the phenotypes of these interstitial PDGF-C expressing cells. However, serial immunohistochemical staining detected ED-1+ macrophages in a similar distribution as PDGF-C-expressing cells (Figure 6).
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In renal disease, one of the notable findings was a marked and apparent de novo upregulation of PDGF-C during the proliferative response phase of anti-Thy 1.1-induced mesangioproliferative glomerulonephritis. The upregulation appeared to selectively label activated mesangial cells and as such was reminiscent of findings with PDGF-A and -B in glomerular disease (5,6). Cultured mesangial cells express both PDGF receptors, and both ligands, PDGF-A and PDGF-B, can induce proliferation of this cell type, although PDGF-B is much more potent (5,6). A central role particularly of the PDGF B-chain in mediating mesangial cell proliferation and matrix overproduction in vivo has been documented in several studies (5,6). Here we identify PDGF-C as the third family member that is capable of inducing mesangial cell proliferation in vitro with a mitogenic activity that is more potent than PDGF-AA yet lower than that of PDGF-BB. Additionally, our study identifies mesangial cells not only as a target but also as a source of PDGF-C production in vitro and in vivo, indicating the existence of an autocrine stimulatory pathway similar to that previously described for PDGF-B (5). To gain further insight into the regulation of PDGF-C in vivo and in particular a potential interplay with PDGF-B, we also assessed the mesangial PDGF-C expression during anti-Thy 1.1 nephritis after specific antagonism of PDGF-B. Although selective inhibition of PDGF-B had a significant effect on mesangial proliferation and matrix accumulation, the expression of mesangial PDGF-C was not altered by PDGF-B inhibition, indicating the existence of different pathways in the regulation of PDGF-B and PDGF-C.
Apart from glomerular mesangial cells, visceral and parietal epithelial cells have been identified as additional glomerular sources of apparent de novo PDGF-C expression in animal models with predominant injury to these cell types. These findings are again reminiscent of findings for PDGF-B, which can be expressed by visceral and parietal glomerular epithelial cells after injury (23,24). In the case of both PDGF-B and -C, the absence of functional in vitro and particularly in vivo studies presently precludes speculations on the role of PDGF-B and -C in these cell types. However, as in the case of PDGF-B (25), it is noteworthy that there was no clear correlation between the degree of glomerular sclerosis and the extent of glomerular epithelial PDGF-C expression.
A significant increase in individual PDGF-C-expressing cells was seen at sites of fibrosing interstitial injury that was most prominent in the hypercholesterolemic, diabetic rats. Although the exact cellular origin of PDGF-C expression remains to be determined, this study identified monocytes/macrophages as potential sources of PDGF-C in this scenario. However, the additional expression of PDGF-C in a small subset of fibroblasts or myofibroblasts cannot be formally excluded. Li et al. (7) identified PDGF-C as a potent mitogen for cultured fibroblast cells, and Gilbertson et al. (8) have been able to demonstrate PDGF-C-induced proliferation of several mesenchymal cell types, including human adventitial fibroblasts in vitro. Li et al. (7) have furthermore linked PDGF-C expression with fibrosis. Transgenic expression of PDGF-C in the mouse heart, using the promoter for the -myosin heavy chain, induced strong proliferation of cardiac fibroblasts and subsequent interstitial expansion with features of interstitial fibrosis (7). In the renal interstitium, the PDGF -receptor is constitutively expressed (7) and PDGF ß-receptor is upregulated in progressive renal failure (19). Therefore, the de novo occurrence of PDGF-C-producing cells in damaged renal tubulointerstitium may contribute to the pathogenesis of renal tubulointerstitial fibrosis.
In conclusion, this study links pathologic overexpression of the new growth factor PDGF-C to the induction of mesangial cell proliferation in vivo and in vitro as well as to tubulointerstitial inflammation and fibrosis. Compounds that specifically inhibit PDGF-C in vivo will help to further define the role of PDGF-C in the concert of actions of the members of the PDGF family of cytokines.
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