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BASIC SCIENCE |
Mitogen-Activated Protein Kinase Activation in Renal Fibrosis
*Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; and Scios Inc., San Francisco, California.
Correspondence to: Dr. Cosimo Stambe, Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Australia, 3168. Phone: 61-3-95943568; Fax: 61-3-9594-3650; E-mail: cosimo.stambe{at}med.monash.edu.au
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Abstract |
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, NPC 31169, from the time of UUO surgery until being killed 7 d later. Compared with vehicle, NPC 31169–treated rats had a significant reduction in renal fibrosis assessed by interstitial volume, collagen IV deposition, and mRNA levels. This was primarily due to a reduction in the accumulation of interstitial myofibroblasts, as shown by a reduction in the area of immunostaining for alpha–smooth muscle actin and heat shock protein 47. The increase in renal TGF-
1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38 MAPK plays an important role in renal fibrosis, acting downstream of TGF-1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis. |
Introduction |
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The p38 MAPK pathway is activated by multiple stimuli, including IL-1, TNF-, lipopolysaccharide, ultraviolet light, and TGF-1. Activation results in sequential phosphorylation and activation of a series of upstream kinases, resulting in phosphorylation and activation of p38 MAPK (1–3). Currently, four isoforms of p38 are described, , , 
and 
, which share a degree of amino acid sequence homology but differ in cell and tissue distribution (4–7). The , , and isoforms are predominant in the kidney. Furthermore, the and isoforms are present in macrophages, T cells (8), and myofibroblasts (9), cell types that infiltrate the kidney in disease. Phosphorylation of p38 results in its translocation to the nucleus and the activation of transcription factors involved in production of proinflammatory mediators (10,11) and extracellular matrix proteins (12–14).
TGF-1 is an important profibrotic mediator critical for collagen and matrix deposition (15), and TGF-1 has been shown in vitro to be associated with the activation of p38 (16,17). Recent evidence has suggested that TGF-1 activates the p38 and isoform of the p38 MAPK pathway via MKK3, and that TGF-1–stimulated mesangial cells from MKK3-deficient mice had a reduction in pro–alpha I collagen expression compared with wild-type mice (18). In addition, p38 MAPK activation has been associated with production and secretion of TGF-1 and extracellular matrix proteins (19). It is likely, therefore, that p38 MAPK activation has an important role in in vivo fibrosis independent of its proinflammatory effects, as both a downstream target of TGF-1 signaling and an inducer of TGF-1. In addition, connective tissue growth factor (CTGF), induced by TGF-1 signaling, is an important mediator of collagen and tissue matrix protein production (20), but its relationship to p38 MAPK activation has not previously been studied.
p38 MAPK activation has been demonstrated in the lung of patients with pulmonary fibrosis (21). Blockade of p38 has been demonstrated to inhibit TGF-1–induced collagen expression in fibroblasts, hepatic cells, and mesangial cells in vitro (22–24). In animal models of toxic inflammatory lung injury, blockade of p38 MAPK has been shown to reduce fibrosis (25,26). Fibrosis in these animal models is in part as a consequence of an initial inflammatory insult, and inhibition of tissue inflammation by p38 blockade may have contributed to a reduction in tissue fibrosis. Thus, direct evidence of a role for p38 MAPK activation in fibrosis in vivo is lacking.
We thus examined activation of p38 MAPK in a model of renal fibrosis induced by a noninflammatory surgical insult, unilateral ureteric obstruction (UUO) and localized activation of the pathway to cells within obstructed kidney. With the use of a specific inhibitor of p38, NPC 31169, we examined the contribution of p38 activation to the development of renal fibrosis.
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Antibodies
The following mouse monoclonal antibodies were used in this study: anti-phospho p38 (p-p38, Sigma-Aldrich, St. Louis, MO) raised against the dual phosphorylated tyrosine and threonine residues of the p38 peptide and recognizing all of the phosphorylated p38 isoforms; anti-p38 (anti-SAPK2a, Upstate, New York, NY), recognizing the nonphosphorylated and phosphorylated p38 isoform; ED1, anti-CD68 recognizing rat macrophages (Serotec, Oxford, UK); OX-1, anti-CD45 supernatant recognizing rat leukocytes; R73, recognizing rat lymphocytes; anti–1-tubulin (Sigma-Aldrich); 1A4, anti–alpha smooth muscle actin (-sma, Sigma-Aldrich); anti-collagen IV (Dako, Glostrup, Denmark); and anti–heat shock protein 47 (Hsp47) recognizing rat collagen chaperone protein (Stressgene Biotechnologies, Victoria, Canada). The following rabbit polyclonal antibody was used: anti-TGF-1 (Santa Cruz, Santa Cruz, CA). Horseradish peroxidase and alkaline phosphatase–conjugated goat anti-mouse IgG, and peroxidase-conjugated mouse anti-peroxidase complexes (PAP) were purchased from Dako.
Western Blot Analysis
At the time the animals were killed, the obstructed kidney from each animal was crushed and suspended in 1.0 ml of lysis buffer containing 10 mM Tris-HCl pH 7.4, 100 mmol NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 2 mM Na3VO4, 0.1% SDS, 1% Triton X-100, 0.5% deoxycholate, 1 mM phenylmethylsulfonyl fluoride, and 10% proteinase inhibitor (Sigma-Aldrich) and left on ice for 15 min, vortexing every 2 min. The samples were centrifuged at 14,000 rpm for 10 min and the supernatant stored at -80°C. Protein estimations were performed with a Bradford assay (Pierce, Rockford, IL). Protein was loaded at 100 µg per well and separated by SDS-PAGE on a 12.5% acrylamide gel. Gels were electroblotted onto a PVDF membrane, and the blots were incubated for 2 h in 20 ml of blocking buffer (50 mM Tris-HCl, 350 mM NaCl, 0.5% Tween20 with 5% skim milk). Blots were then washed three times in wash buffer (50 mM Tris-HCl, 350 mM NaCl, 0.02% Tween20 pH 7.5) and incubated with either anti-p38 (1 µg/ml) or anti–p-p38 (2 µg/ml) in 5% BSA in wash buffer overnight at 4°C. Blots were washed three times, then incubated with horseradish peroxidase conjugated goat anti-mouse IgG for 2 h at room temperature, washed three times, and the membrane-bound antibody detected by Supersignal West Pico chemiluminescent substrate (Pierce) and captured on x-ray film.
To determine the equivalence of protein loading, membranes were stripped with x1 stripping buffer (Chemicon International, Temecula, CA), blocked with 20 ml of blocking buffer for 2 h, and then probed with anti–1-tubulin (1:2000) in 5% BSA in wash buffer overnight. Membranes were washed three times and incubated with horseradish peroxidase conjugated goat anti-mouse IgG, washed in wash buffer three times, and developed with chemiluminescence (Pierce) and captured on x-ray film. Densitometry analysis was performed by a Gel Pro analyser program (Media Cybernetics, Silver Spring, MD).
Immunohistochemistry
Slices of the obstructed kidney were fixed in 4% buffered formalin (for p-p38, CD68, 1A4, Hsp47, fibronectin, and TGF-1 immunostaining) and embedded in paraffin. Four-micron sections were cut, dewaxed in histosol, and rehydrated. Alternatively, tissue was fixed in 2% paraformaldehyde-lysine-periodate for 3.5 h, snap-frozen in OCT, and 4-µm cryostat sections cut for p38, CD45, T cell, and collagen IV immunostaining. Immunohistochemical staining was performed as described previously (27). Briefly, the sections were microwave oven–heated in a Dako microwave buffer for 10 min and allowed to cool. All sections were washed in PBS, blocked with 10% normal sheep serum plus 10% FCS in PBS for 30 min at room temperature, and incubated overnight at 4°C with anti–p-p38, anti-p38, anti-CD68, anti-CD45, R73, 1A4, anti-collagen IV, anti-Hsp47, or anti–TGF-1 in 10% normal rat serum, 1% BSA in PBS. Sections were subsequently washed once in PBS, endogenous peroxidase inactivated in 1% H2O2 in methanol for 20 min, incubated with horseradish peroxidase–conjugated goat anti-mouse (or rabbit) IgG followed by mouse (or rabbit) PAP, and developed with 3,3-diamenobenzidine to produce a brown color. We have previously demonstrated specificity of p-p38 immunostaining by using absorption of the p-p38 antibody with p-p38 or irrelevant phosphopeptides (28).
When double labeling, the sections were immunostained by means of the PAP method described above and then were microwave oven–heated, blocked with 10% normal sheep serum and 10% FCS in PBS, and incubated with 1A4 (1:2000) overnight at 4°C in 10% normal rat serum and 1% BSA, incubated with horseradish peroxidase–conjugated goat anti-mouse IgG followed by mouse PAP, and developed with Vector SG (Vector Laboratories, Burlingame, CA) to produce a gray color.
NPC 31169 Kinase Assays
NPC 31169 was developed by Scios Inc. (San Francisco, CA) and inhibits the active (phosphorylated) form of p38 MAPK. Specificity for p38 inhibition was determined in kinase assays. Individual kinases were isolated from cell lysates by immunoprecipitation. Kinase assays were performed as described previously (29). Briefly, kinases were incubated with their specific target substrates together with 0.1 mM [g32P]ATP for 10 min at 30°C in the presence of increasing concentrations of NPC 31169. Protein was precipitated, washed in 50 mM phosphoric acid to remove ATP, and radioactivity counted. The concentration of NPC 31169 required to inhibit kinase activity by 50% was recorded as a 50% inhibitory concentration value (Table 1).
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MAPK Blockade in Rat UUO
Quantification of Interstitial Volume, Leukocyte and Myofibroblast Accumulation, and Extracellular Matrix Deposition
All analyses were performed on blinded slides. Interstitial volume was assessed on 3-µm periodic acid–Schiff–stained formalin-fixed sections at x250 magnification by counting the number of intersecting points that fall between tubules on a defined 100-point grid. Glomeruli and large vessels were excluded. A total of 10 fields per animal were counted and the results expressed as a percentage of the total number of grid points counted. Interstitial T cells and macrophages were scored by counting the number of immunostained cells per high-power field (x400) on 20 fields per animal and expressed as cells per square millimeter. -sma, collagen IV, and TGF-1 staining were assessed by image analysis of 20 fields (x250 magnification), excluding glomeruli, per animal (Image-Pro Plus Software, Media Cybernetics) and the results expressed as the percentage of the area of the cortex stained. Interstitial Hsp47 staining was scored by counting the number of intersecting points of a grid falling on positively stained interstitial cells on 4-µm formalin-fixed sections at x250 magnification. A total of 20 fields per animal were counted and the results expressed as a percentage of the number of Hsp47-positive points per 1000 points counted. Glomeruli and large vessels were excluded.
Northern Blot Analysis
Probes used for Northern blot analysis were as follows. Rat -sma, TGF-1, and glyceraldehyde phosphate dehydrogenase (GAPDH) cDNA were cloned into pMOSBlueT-vector (Amersham, Buckinghamshire, England). Mouse collagen 1 (IV) and rat CTGF were cloned into pCRII-TOPO vector (InVitrogen, San Diego, CA). Except for GAPDH, anti-sense cRNA probes were labeled with digoxigenin (DIG)–UTP (Roche, Mannheim, Germany) by using either T7 RNA polymerase for pMOS-Blue T-vector or SP6 RNA polymerase for the cDNA inserts cloned into pCRII-TOPO vectors. The antisense GAPDH cRNA probe was labeled with fluorescein (FITC)–UTP (Roche) by using the T7 RNA polymerase.
Total RNA from normal and obstructed kidney was extracted with TriZol (InVitrogen) according to the manufacturer’s instructions. A total of 15 µg of RNA was denatured with glyoxal and DMSO and size-fractionated on 1.2% agarose gels and capillary-blotted onto nylon membranes (Amersham). Membranes were hybridized in DIG Easy Hybridization Buffer (Roche) with either DIG-labeled RNA probes or FITC-labeled cRNA probes at 68°C. After hybridization, membranes were finally washed in 0.1x SSC/0.1% SDS at 68°C. Bound probes were detected by means of alkaline phosphatase conjugated sheep anti-DIG antibody (Fab) or sheep anti-FITC antibody and then incubated with CDP-Star (Roche) reagent and chemiluminescence captured on Kodak BMR film. Densitometry analysis was performed by the Gel Pro analyzer program (Media Cybernetics).
Statistical Analyses
Data are presented as mean ±1 SD. Comparisons were made between groups of animals by ANOVA by the Bonferroni correction for multiple comparisons (GraphPad Software, San Diego, CA).
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and p-p38 were present in whole kidney lysates of normal animals (Figure 2, a and b). Immunostaining demonstrated that p38 was localized to the luminal surface of many tubules in normal kidney (Figure 3a). In most tubules with luminal staining, nuclear staining for p38 was not seen, suggesting that p38 was not activated in these cells. Conversely, nuclear, but not luminal, p38 staining was seen in a few tubules. Taken together, these data suggest tubular activation and nuclear translocation of cytoplasmic p38 in a few tubules of normal rat kidney (Figure 3a). p-p38 was localized to the nuclei of some tubular cells in normal kidney, with variation in the intensity of staining (Figure 3e).
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protein was increased within 6 h of ureteric ligation compared with normal, and continued to increase up to day 7 of obstruction (Figure 2a). At 6 h UUO, there was a loss of p38 luminal staining within dilated tubules, with an increase in nuclear staining in these tubules (Figure 3b). This immunostaining pattern was more pronounced at day 7 UUO, in which luminal staining was absent in many tubules with increased nuclear staining (Figure 3c) By Western blot test, there was an increase in p-p38 seen in the obstructed kidney compared with normal, being elevated at 6 h after UUO and increasing to 13-fold above normal by day 7 (Figure 2b). The number of p-p38–positive nuclei was increased in dilated tubules at 6 h and day 7 UUO (Figure 3, f and g).
The obstructed kidney is characterized by an interstitial infiltrate of myofibroblasts, macrophages, and lymphocytes. Myofibroblasts detected by immunostaining for a cytoplasmic marker, -sma, were positive for both p38 and p-p38 in a nuclear staining pattern (Figure 3, d and h). -sma staining was restricted to interstitial cells and blood vessels (Figure 3, d and h). Serum creatinine estimations at the time of death were normal in drug- and vehicle-treated animals, suggesting that significant NPC 31169 nephrotoxicity in the normal nonobstructed contralateral kidney does not occur (51.5 ± 6.3 µmol/L in drug-treated animals versus 53.2 ± 7.1 µmol/L in vehicle-treated animals; P = 0.23). No toxicity in terms of body weight, condition of the animal, hemoglobin, white blood cell count, and platelet count was seen (data not shown).
p38 Blockade Reduces Interstitial Myofibroblast Accumulation and Renal Fibrosis
To assess the functional contribution of p38 MAPK activation to the development of interstitial fibrosis in UUO, we treated animals with a specific inhibitor of p38, NPC 31169 (Table 1). Compared with vehicle-treated animals, NPC 31169 treatment reduced interstitial volume by 56% in rats at day 7 after UUO (Figure 4a). In addition, there was a 51% reduction in collagen IV mRNA expression in whole kidney with NPC 31169 treatment (Figure 5a) and a 29% (percentage of area stained) reduction in matrix collagen IV immunostaining compared with vehicle treatment (Figure 6, a–c). This reduction was not attributed to a reduction in infiltrating leukocytes because the number of interstitial macrophages and lymphocytes were not different in NPC 31169–treated animals compared with vehicle-treated animals (Figure 4b).
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-sma mRNA expression in whole kidney by Northern blot test (Figure 5b) and a 44% reduction in interstitial -sma immunostaining as determined by the percentage of area of cortex stained (Figure 6, d–f) compared with vehicle-treated animals. Collagen production and secretion by both myofibroblasts and tubular cells are associated with Hsp47 production. Interstitial Hsp47 may therefore be a useful marker of the number of myofibroblasts present. In animals treated with NPC 31169, interstitial Hsp47 immunostaining was reduced by 45% compared with vehicle-treated animals (point counting, Figure 6, g–i).
Upregulation of TGF-1 Production in UUO Is Not Affected by p38 MAPK Blockade
To determine whether the reduction in renal fibrosis with p38 blockade was associated with an alteration in TGF-1, we examined TGF-1 protein production by immunostaining and TGF-1 mRNA by Northern blot test. Immunohistochemistry of normal kidney shows weak TGF-1 staining in a few cortical tubules (data not shown). In obstructed kidney, there was strong immunostaining of TGF-1 in dilated and injured tubules, and to a much smaller degree the interstitium. Compared with vehicle-treated animals, TGF-1 immunostaining, as determined by the percentage of area of cortex stained, is unaltered with NPC 31169 treatment at day 7 obstruction (Figure 7, a–c). Northern blot analysis demonstrated an increase in TGF-1 mRNA at day 7 obstruction, which was unaffected by NPC 31169 treatment (Figure 7d). In addition, we examined CTGF, a downstream target of TGF-1 involved in extracellular matrix production. Compared with vehicle-treated animals, CTGF mRNA expression was reduced by 62% in NPC 31169–treated animals at day 7 UUO (Figure 7e).
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and activated p38 (p-p38) in obstructed kidney through a time course of UUO. By immunolocalization, we demonstrated a loss of luminal p38 with a concomitant increase in nuclear p38 and p-p38 within injured and dilated tubules. This staining pattern suggests that cytoplasmic p38 is activated by phosphorylation and translocates to the nucleus of the injured tubular cell during obstruction. In addition, we localized both p38 and p-p38 to nuclei of interstitial myofibroblasts—cell types central to the development of interstitial fibrosis in the obstructed kidney. With the use of a specific inhibitor of p38, we demonstrated a functional role for p38 MAPK pathway activation in renal fibrosis, independent of TGF-1 protein and mRNA levels, but with a reduction in CTGF mRNA expression.
The reduction in extracellular matrix deposition with p38 MAPK blockade in UUO was proportional to the reduction in interstitial myofibroblast accumulation, as demonstrated by a reduction in -sma staining and mRNA expression. However, recent evidence has suggested that p38 may be involved in TGF-1–induced -sma production, and therefore, -sma may not necessarily reflect the amount of tissue myofibroblast infiltration (30,31). To confirm our findings, we assessed interstitial Hsp47, a collagen chaperone protein produced by myofibroblasts during collagen production and independent of p38 activation. The amount of interstitial Hsp47 protein may therefore more accurately represent the number of interstitial myofibroblasts present. Compared with vehicle-treated animals, treatment with NPC 31169 showed a reduction in interstitial Hsp47 staining, consistent with the degree of reduction in interstitial -sma–positive cell accumulation.
This reduction in interstitial myofibroblast accumulation may be as a result of inhibition of myofibroblast migration or a decrease in myofibroblast transdifferentiation of tubular and smooth muscle cells. Previous in vitro reports have demonstrated the importance of p38 MAPK activation to PDGF-BB mediated migration of hepatic myofibroblasts (32). Furthermore, TGF-1 has been demonstrated to induce myofibroblast transdifferentiation of tubular cells both in vitro (33) and in UUO (34) and TGF-1–induced mammary epithelial cell migration and subsequent fibroblast transdifferentiation is dependent on p38 MAPK activation (35). It is therefore possible that p38 MAPK inhibition in this study resulted in a reduction in interstitial myofibroblast accumulation by interfering with both TGF-1 mediated myofibroblast and epithelial migration, and myofibroblast transdifferention of tubular cells and smooth muscle cells.
p38 MAPK activation occurred within tubules and infiltrating myofibroblasts of the obstructed kidney, and p38 MAPK blockade may have inhibited collagen production in this study via an effect on either or both of these cell types. In vitro studies have demonstrated TGF-1–induced collagen expression in myoblasts via p38 MAPK activation (36). TGF-1–induced extracellular matrix production by neonatal rat primary cardiac fibroblasts is inhibited by SB203055, an inhibitor of the p38 pathway (37), and activated mutants of MKK3 and MKK6, both upstream kinases of the p38 pathway, is associated with an increase in cardiac fibrosis (38). Proximal renal tubular cells are a known source of TGF-1 and may promote peritubular myofibroblast collagen production and interstitial fibrosis (39). In addition, these cells may act as effectors for collagen IV production and deposition, an effect mediated by TGF-1 (40).
Despite recent in vitro evidence of a role for p38 activation in TGF-1 production (19), we were unable to demonstrate this in vivo. In our study, TGF-1 mRNA expression and protein is increased in obstructed kidney and unaffected by p38 MAPK blockade. TGF-1 was localized predominantly to the dilated and injured tubules of obstructed kidney. The inability to suppress TGF-1 production by p38 blockade is consistent with recent studies demonstrating that angiotensin II–induced TGF-1 production in vascular smooth muscle cells is mediated via the extracellular signal-related kinase MAPK and protein kinase C pathways (41,42).
CTGF is a downstream effector of TGF-1 signaling and is important in the production of extracellular matrix proteins. It is localized to both tubular epithelial cells and the interstitium in UUO, and TGF-1–induced fibronectin production is reduced with CTGF oligonucleotide antisense transfection of cultured renal fibroblasts (43). In this study, CTGF mRNA expression in vivo is reduced with p38 blockade and parallels the reduction in myofibroblast accumulation. From this study, it is not possible to discern whether the reduction in CTGF mRNA expression is as a consequence of the reduction in the number of interstitial myofibroblasts or whether there is a direct inhibitory effect on myofibroblast CTGF production with p38 blockade.
In UUO and other models of renal fibrosis, angiotensin II contributes to the development and progression of renal fibrosis by promoting the synthesis of growth factors and cytokines, including TGF-1 (44) and TNF- (45–47). TNF- receptor I–deficient mice and pharmacologic inhibition of TNF- receptor I partially reduces renal fibrosis in UUO (48). Furthermore, TNF- is both a stimulus for p38 activation and is produced and secreted in response to p38 activation. The p38 MAPK is a common downstream target of TGF-1 and TNF- signaling in UUO, and blockade of p38 may therefore reduce interstitial fibrosis by inhibition of TGF-1- and TNF-–dependent extracellular matrix production.
UUO results in severe renal fibrosis as a consequence of a constant surgical insult. In this model, p38 blockade was associated with a significant reduction in fibrosis despite the presence of persistent stimulus for extracellular matrix production, ureteric ligation. Furthermore, increased TGF-1 mRNA expression or protein production in UUO was not reduced after p38 blockade, suggesting that p38 activation mediates fibrosis downstream or independent of TGF-1.
Two recent studies have demonstrated a reduction in bleomycin-induced pulmonary fibrosis with p38 inhibitors (25,26). Fibrosis after bleomycin is dependent on leukocyte mediated pulmonary injury (49,50). Thus, these studies cannot determine whether p38 blockade inhibited lung fibrosis through an action on leukocytes or through direct action on the myofibroblasts. We have demonstrated a reduction in fibrosis in a model of surgically mediated renal injury, consistent with a recent report demonstrating a reduction in cardiac fibrosis by using a transgenic approach to inhibit the p38 MAPK pathway in a noninflammatory, pressure-overload model of cardiac hypertrophy and fibrosis (51).
In summary, we have identified a direct functional role for p38 MAPK activation in progressive renal fibrosis. p38 and p-p38 were increased in obstructed kidney, and we localized p38 MAPK activation to dilated and injured tubules, and infiltrating myofibroblasts. With the use of a novel and selective inhibitor of p38, we were able to inhibit interstitial myofibroblast accumulation, reduce collagen IV mRNA expression and protein deposition, and reduce CTGF mRNA expression in spite of a continued increase in TGF-1 mRNA expression and protein production. Therefore, p38 MAPK blockade may be a therapeutic option for the treatment of renal fibrosis.
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