Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Immunology and Pathology
You have accessRestricted Access

Role of Mast Cell Tryptase in Renal Interstitial Fibrosis

SHUJI KONDO, SHOJI KAGAMI, HIROSHI KIDO, FRANK STRUTZ, GERHARD A. MÜLLER and YASUHIRO KURODA
JASN August 2001, 12 (8) 1668-1676; DOI: https://doi.org/10.1681/ASN.V1281668
SHUJI KONDO
*
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
SHOJI KAGAMI
*
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
HIROSHI KIDO
†
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
FRANK STRUTZ
‡
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
GERHARD A. MÜLLER
‡
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
YASUHIRO KURODA
*
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

Abstract. Renal interstitial fibrosis is characterized by increased proliferation of fibroblasts and excessive accumulation of extracellular matrix. Mast cell tryptase has been implicated in the development of tissue fibrosis in skin and lungs. However, the significance of mast cell tryptase in human renal diseases has not been investigated. The potential role of mast cell-derived tryptase in the development of renal fibrosis was studied using immunohistochemical techniques and cultured human renal fibroblast cell lines. Semiquantitative immunostaining analysis of samples from 70 patients with several renal diseases, including IgA glomerulonephritis (GN) (n = 30), non-IgA GN (n = 5), membranous GN (n = 5), focal segmental glomerulosclerosis (n = 4), minor glomerular abnormalities (n = 5), lupus nephritis (n = 3), and acute or chronic tubulointerstitial nephritis (n = 18), revealed that the degree of renal interstitial fibrosis was well correlated with the number of infiltrating tryptase-positive mast cells (P < 0.01). Mast cells could not be detected in damaged glomeruli in any form of renal disease. [3H]Thymidine uptake experiments demonstrated that DNA synthesis by cultured renal fibroblasts was increased with the concentration of tryptase (0.5 to 5 nM) coincubated with heparin and was suppressed by coincubation with the protease inhibitors leupeptin and benzamidine hydrochloride. Tryptase alone also increased DNA synthesis by fibroblasts but exhibited less effectiveness, compared with the combination of tryptase and heparin. Conversely, heparin alone suppressed DNA synthesis by fibroblasts. Metabolic [35S]methionine-labeling experiments with cultured renal fibroblasts indicated that tryptase increased the synthesis of fibronectin and collagen type I, in a dose-dependent manner. These findings suggest that mast cell tryptase plays a role in the proliferation and extracellular matrix protein production of renal interstitial fibroblasts and thus contributes to the development of renal interstitial fibrosis.

Renal tubulointerstitial fibrosis is the common final pathway leading to end-stage renal failure. The severity of tubulointerstitial inflammation and fibrosis has long been considered to be a crucial determinant of progressive renal injury and long-term prognoses for both human and experimental glomerulonephritis (GN) (1,2,3). Fibroblasts are the main effector cells in renal interstitial fibrosis. Under normal conditions, only a small proportion of these cells participate in the synthesis and deposition of extracellular matrix (ECM) proteins, mainly collagen type I (COL I), to maintain tubulointerstitial integrity (4). In pathologic conditions, fibroblasts proliferate, migrate, and synthesize growth factors as well as matrix proteins, contributing to the development of renal interstitial fibrosis (5).

Recently, several lines of evidence have suggested the participation of mast cells in fibroblast proliferation in a number of organs. Increased numbers of mast cells are observed in close proximity to proliferating fibroblasts in healing wounds and in fibrotic lesions of lungs, vessel walls, and skin in human subjects (6,7,8,9). The most abundant product of human mast cells is the serine protease tryptase. Tryptase is a tetrameric serine protease with a molecular size of 134 kD; it is composed of four monomers of 32 to 34 kD, each with one catalytic site (10). Its presence is restricted almost exclusively to mast cells, where tryptase exists within the secretary granules in a complex with heparin proteoglycan (11). Tryptase has various biologic activities, such as fibrinogenolysis, augmentation of histamine-mediated contractility of airway smooth muscle, and degradation of vasoactive intestinal peptide (12,13,14). Importantly, tryptase has been demonstrated to be mitogenic for fibroblasts, smooth muscle cells, and bronchial epithelial cells (15,16,17). Recent studies have indicated that tryptase-positive mast cells may be involved in renal interstitial injury (18,19,20). However, the significance of mast cell tryptase in human renal interstitial fibrosis has not been investigated. To evaluate the role of mast cell tryptase, we first examined the localization of tryptase-positive mast cells in various types of human renal diseases. In addition, we investigated the possible role of tryptase in renal fibroblast proliferation and matrix protein synthesis in vitro.

We report for the first time that mast cell tryptase may have a role in the development of renal interstitial fibrosis, because the number of infiltrating tryptase-positive mast cells was well correlated with the degree of interstitial scarring. Furthermore, we observed that mast cell tryptase is a mitogen and fibrogenic factor for human renal fibroblasts.

Materials and Methods

Patients

Immunostaining was performed on formalin-fixed, paraffin-embedded sections from 70 patients with several renal diseases, including IgA GN (n = 30), non-IgA GN (n = 5), membranous GN (n = 5), focal segmental glomerulosclerosis (n = 4), minor glomerular abnormalities (n = 5), lupus nephritis (n = 3), and acute or chronic tubulointerstitial nephritis (TIN) (n = 18).

Immunohistochemical Studies

Immunohistochemical studies were performed as described previously (21). Formalin-fixed tissue sections were deparaffinized with xylene and rehydrated with graded ethanols. Endogenous peroxidase was blocked with hydrogen peroxide, and the samples were then rinsed in phosphate-buffered saline (PBS). To yield adequate signals with the respective antibodies, the slides were trypsinized for 30 min at 37°C. For reduction of background labeling, the sections were blocked for 30 min in normal horse serum. The sections were incubated for 24 h at 4°C with mouse anti-human mast cell tryptase monoclonal antibody (Chemicon International, Temecula, CA) diluted in PBS containing 1% bovine serum albumin (1:1000). It has been demonstrated that tryptase serves as a selective marker that distinguishes mast cells from other cell types (11). After washing with PBS, the tissue was incubated with biotinylated secondary antibody, avidin-biotin-peroxidase complex (ABC Elite; Vector Laboratories, Burlingame, CA), and then 3,3′-diaminobenzidine (Dojindo, Kumamoto, Japan). Each section was counterstained with Mayer's hematoxylin (Wako, Tokyo, Japan), dehydrated, and coverslipped. A total of 10 consecutive nonoverlapping interstitial areas (area, 0.625 mm2) were analyzed in each section of the biopsy (18). Tubulointerstitial damage was estimated on the basis of the degree of tubulointerstitial fibrosis, as primarily judged using Azan-Mallory staining. The degree of tubulointerstitial fibrosis was semiquantitatively graded by two independent observers and was expressed as a ratio of the area of fibrosis to that of the renal interstitium in biopsy sections.

Cell Culture

Human renal interstitial fibroblast cell lines were established as described previously (22). Briefly, human renal interstitial fibroblasts were obtained from the medullary part of a kidney biopsy with histologically proven GN and interstitial fibrosis. Fibroblast clones, as identified by morphologic criteria, were subcultured in Dulbecco's modified Eagle's medium (Sigma Chemical Co., St. Louis, MO) with 10% fetal calf serum (FCS) (HyClone, Logan, UT). Clones of these early-passage human renal fibroblasts were immortalized by transfection with the SV40 plasmid pSVgpt (23). Stable cell lines of these SV40-immortalized fibroblasts were obtained by repeated subcloning of transfected cells (24). The renal fibroblast cell lines were comparable to the parental nontransformed interstitial fibroblasts, as indicated by similar morphologic features, unchanged patterns of expression of COL I, III, and V, fibronectin (FN), laminin, vimentin, tenascin, and intercellular adhesion molecule-1, and negative immunostaining for cytokeratin, desmin, and factor VIII (24). In addition, these fibroblasts were positive for CD90, a marker for cultured renal fibroblasts (25). The renal fibroblast cell lines (fibrosis-derived renal fibroblasts) were maintained in RPMI 1640 medium (Life Technologies/BRL, Grand Island, NY) containing 2 mM L-glutamine (Sigma), 25 mM Hepes (Sigma), 100 U/ml penicillin, 100 μU/ml streptomycin (Life Technologies/BRL), and 10% FCS. All experiments were performed after 24-h incubations in serum-free RPMI 1640 medium, to achieve fibroblast quiescence.

Proteinase Catalytic Assays

Human tryptase was purchased from Biogenesis (Poole, Dorset, UK). Tryptase activity was assayed using the peptide substrate N-tert-butoxycarbonyl-Phe-Ser-Arg-4-methyl-coumaryl-7-amide (Peptide Institute, Japan). Tryptase activity was expressed in milliunits per milliliter, where 1 U of enzyme activity was defined as the amount degrading 1 μmol of substrate per minute at 25°C (26). The specific activity of the tryptase preparations used in this study was 1.64 mU/μg.

Cell Proliferation Studies

Confluent human renal fibroblasts were detached from culture flasks with trypsin-ethylenediaminetetraacetate (Life Technologies/BRL) and were seeded into 24-well plates (Costar Corp., Cambridge, MA) at a density of 4 × 104 cells/ml, in RPMI 1640 medium containing 10% FCS. At subconfluence (60%), the medium was replaced with serum-free medium for 24 h. The cells were treated with tryptase in the presence of 1 U/ml heparin (Sigma) for 24 h and were radiolabeled with 0.5 μCi/well [methyl-3H]thymidine (Dupont/New England Nuclear, Boston, MA) for the last 12 h. The cells were collected and counted in a liquid scintillation counter (27). In experiments with protease inhibitors, tryptase was preincubated with 50 μg/ml leupeptin (a nonselective serine protease inhibitor; Sigma) or 50 μM benzamidine hydrochloride (a relatively selective tryptase inhibitor; Sigma) for 1 h at 4°C (28). Similar experiments studying DNA synthesis by fibroblasts were performed by incubating cells with either trypsin or tryptase in the presence or absence of heparin or with heparin alone. Cell proliferation in response to incubation with tryptase was also monitored by cell counting with a hemocytometer.

[35S]Methionine-Labeling of Cells and Measurement of ECM Protein Synthesis

Growth-arrested renal fibroblasts in six-well culture plates (Costar Corp.) were incubated for 24 h in methionine-free medium containing either various concentrations of tryptase with 1 U/ml heparin or heparin alone and were metabolically labeled with 100 μCi/ml [35S]methionine (Dupont) for the last 18 h. For immunoprecipitation and gelatin-Sepharose absorption assays, the medium was collected and centrifuged for removal of cellular debris. Radiolabeled protein in the supernatant was quantified by counting, and a standard amount of radioactivity was used in the immunoprecipitation assays. Aliquots (150 μl) of the radiolabeled medium were diluted with 800 μl of RIPA buffer [25 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1% sodium dodecyl sulfate (SDS), 0.5% Triton X-100, 0.5% deoxycholate]. For removal of nonspecific binding, 10 μl of normal rabbit serum and 50 μl of protein A-Sepharose (Pharmacia LKB Biotechnology, Uppsala, Sweden) were added, and tubes were incubated and centrifuged. Then, 10 μl of a rabbit antibody to human COL I (Chemicon International) was added to the supernatant, and the mixture was incubated for 16 h at 4°C. Immune complexes were recovered by binding to protein A-Sepharose beads (Pharmacia LKB Biotechnology). Beads were washed three times with RIPA buffer, and the immunoprecipitates were analyzed by electrophoresis on 4 to 12% SDS-polyacrylamide gels under reducing conditions, as described previously (29,30). Gelatin-Sepharose was used to isolate FN from the radiolabeled medium, as described previously (31). Briefly, 50 μl of the gelatin-Sepharose suspension was added to each sample, followed by incubation for 16 h at 4°C. The gelatin-Sepharose beads were recovered by centrifugation and washed three times with RIPA buffer. FN was released by resuspension of the beads in electrophoresis sample buffer for 3 min at 100°C, under heating conditions, and was analyzed by electrophoresis, as described above.

Northern Blot Analyses

Growth-arrested fibroblasts were treated for 24 h with either various concentrations of tryptase with 1 U/ml heparin or heparin alone. Total cellular RNA was isolated from the fibroblasts using RNAzol (Biotex Laboratories, Houston, TX). For Northern blot analysis, RNA was denatured and fractionated by electrophoresis through a 1.2% agarose gel (20 μg/lane) and was then transferred to a Hybond nylon membrane (Amersham, Buckinghamshire, UK). Nucleic acids were immobilized by ultraviolet irradiation (Stratagene, La Jolla, CA) and hybridized with 1 × 106 cpm/ml 32P-labeled cDNA probes in hybridization buffer (50% formamide, 19% Denhardt's solution, 0.1% SDS, 5× SSC, 200 μg/ml denatured salmon sperm DNA). The cDNA probes were radiolabeled with [32P]dCTP by random oligonucleotide priming (Boehringer Mannheim Biochemicals, Indianapolis, IN). The cDNA probes used in this study included a rat α1 COL I cDNA and, for normalization of the signals obtained with the cDNA probes, a rat glyceraldehyde-3-phosphate dehydrogenase cDNA; the probes specifically bind to human α1 COL I mRNA and human glyceraldehyde-3-phosphate dehydrogenase cDNA, respectively (32). The hybridization products were observed by autoradiography. Densitometric scans were obtained from autoradiographs, for quantification of hybridization intensity.

Statistical Analyses

Statistical significance in the immunohistochemical studies (defined as P < 0.01) was evaluated using Pearson's correlation coefficients. In vitro findings were presented as mean ± SD, and a value of P < 0.05 was used to establish statistical significance (t test). Triplicate wells were analyzed for cell proliferation studies, and each experiment was performed independently at least twice.

Results

Distribution of Tryptase-Positive Mast Cells and Renal Interstitial Fibrosis

To examine whether mast cell tryptase is involved in renal interstitial fibrosis, we first studied the localization of tryptase-positive mast cells in various renal diseases, using immunohistochemical techniques. Tryptase-positive mast cells could not be detected in patients with minor glomerular abnormalities or GN without renal interstitial fibrosis. However, mast cells were detected in the interstitium for patients with GN accompanied by interstitial fibrosis (Figure 1, A and B). Of note, many mast cells also infiltrated the fibrotic lesion of the renal interstitium in acute or chronic TIN (Figure 1, C and D). Mast cells were not observed in any glomeruli with or without renal diseases. Statistical analysis demonstrated that the degree of renal interstitial fibrosis was well correlated with the numbers of infiltrating mast cells in the interstitium in several renal diseases, including IgA GN, non-IgA GN, membranous GN, focal segmental glomerulosclerosis, minor glomerular abnormalities, lupus nephritis, and acute or chronic TIN (r = 0.834, P < 0.01) (Figure 2). In particular, better correlations were observed for IgA GN (r = 0.7107) and chronic TIN (r = 0.64).

               Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Immunohistochemical localization of tryptase-positive mast cells in the renal tubulointerstitium. Human mast cells were identified by immunostaining using an anti-human mast cell tryptase monoclonal antibody. These experiments were performed using kidney sections from patients with mild IgA glomerulonephritis (GN) (A), moderate IgA GN (B), acute tubulointerstitial nephritis (TIN) (C), and chronic TIN (D). Magnification, ×200.

               Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Relationship between the number of infiltrating tryptasepositive mast cells and the degree of renal interstitial fibrosis in IgA GN (n = 30) (○), non-IgA GN (n = 5) (▵), minor glomerular abnormalities (n = 5) (⋄), membranous GN (n = 5) (×), focal segmental glomerulosclerosis (n = 4) (⋄), lupus nephritis (n = 5) (□), acute TIN (n = 9) ([UNK]), and chronic TIN (n = 9) (▴). The degree of renal interstitial fibrosis was significantly correlated with the number of infiltrating mast cells (r = 0.834, P < 0.01).

Mitogenic Response of Human Renal Fibroblasts to Tryptase

To investigate whether mast cell tryptase has mitogenic potential against renal fibroblasts, we examined the effect of purified tryptase on cultured human renal interstitial fibroblasts in [3H]thymidine uptake experiments. It was demonstrated that tryptase was stabilized as an enzymatically active tetramer by association with heparin and dissociated to inactive monomers without heparin (11). A dose-dependent increase in DNA synthesis by renal fibroblasts was observed after treatment with tryptase in the presence of heparin (0.5 to 5.0 nM) (Figure 3A). In addition, [3H]thymidine uptake of fibroblasts stimulated by tryptase, with or without heparin, was examined. The mitogenic activity of fibroblasts treated with tryptase without heparin was decreased, compared with that of cells coincubated with tryptase and heparin, indicating the substantial role of heparin in maintaining tryptase activity (Figure 4). Because heparin is well known to inhibit the growth of various types of cells in vivo and in vitro, we examined the effect of heparin alone on human renal fibroblasts. Heparin suppressed [3H]thymidine uptake by fibroblasts, suggesting that the mitogenic action in renal fibroblasts in this experiment is induced not by heparin but rather by tryptase with heparin (Figure 5). The proteolytic activity of tryptase was similar to that of trypsin, and this action was reported to play a role in the induction of cell signaling events by tryptase (33). Therefore, we performed an experiment to clarify whether trypsin exhibits any mitogenic effect on cultured fibroblasts. A similar dose-dependent increase in DNA synthesis by fibroblasts was observed with incubation with trypsin (10 to 50 ng/ml), but treatment of fibroblasts with higher concentrations of trypsin resulted in cell rounding and detachment from the plates (Figure 6). Finally, we examined whether the proteolytic cell signaling event induced by tryptase and trypsin at the catalytic site was directly involved in their mitogenic effects on fibroblasts. Preincubation of tryptase- or trypsin-stimulated fibroblasts with the protease inhibitor leupeptin (50 μg/ml) or benzamidine hydrochloride (50 μM) resulted in a significant decrease in [3H]thymidine uptake (Figures 3 and 6), indicating that the proteolytic action of tryptase is critical for induction of the mitogenic response in fibroblasts. No significant change in mitogenesis was observed in cells incubated with either leupeptin or benzamidine hydrochloride, compared with vehicletreated control cells (Figures 3 and 6). Similar to [3H]thymidine uptake experiments, cell-counting experiments indicated that treatment of renal fibroblasts with tryptase and heparin significantly increased cell numbers at tryptase doses of 2 and 5 nM (Figure 3B). This increased response to tryptase stimulation was suppressed by coincubation with either leupeptin or benzamidine hydrochloride.

               Figure 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3.

Effects of mast cell tryptase on DNA synthesis by and cell numbers for human renal fibroblasts. Cultured fibroblasts were incubated for 24 h with vehicle control (0), 50 μM benzamidine hydrochloride (+B), 50 μg/ml leupeptin (+L), different concentrations of tryptase (0.5, 2, or 5 nM), 5 nM tryptase and 50 μM benzamidine hydrochloride (5+B), or 5 nM tryptase and 50 μg/ml leupeptin (5+L). Tryptase treatment of fibroblasts always included coincubation with 1 U/ml heparin. (A) [3H]Thymidine uptake during the last 12 h of culture was measured as an index of DNA synthesis. (B) Cell proliferation after each treatment was monitored by cell counting with a hemocytometer. *, P < 0.05, significant difference between untreated fibroblasts and tryptase-treated fibroblasts. Values are mean ± SD.

               Figure 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4.

Comparison of the effects of mast cell tryptase with heparin (□) and without heparin (▪) on DNA synthesis by human renal fibroblasts. Values for [3H]thymidine uptake by renal fibroblasts treated for 24 h with tryptase (0.5 to 5 nM) in the absence or presence of 1 U/ml heparin were compared. The cells were radiolabeled with 0.5 μCi of [3H]thymidine during the last 12 h. *, P, < 0.05, significant difference between untreated fibroblasts and tryptase-treated fibroblasts with heparin; **, P < 0.05, significant difference between untreated fibroblasts and tryptase-treated fibroblasts without heparin. Values are mean ± SD.

               Figure 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5.

Effects of heparin on DNA synthesis by human renal fibroblasts. The [3H]thymidine uptake by fibroblasts treated for 24 h with heparin (1 to 10 U/ml) was examined. The cells were radiolabeled with 0.5 μCi of [3H]thymidine during the last 12 h. *, P < 0.05, significant difference between untreated fibroblasts and heparintreated fibroblasts. Values are mean ± SD.

               Figure 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6.

Effects of trypsin on DNA synthesis by human renal fibroblasts. Cultured fibroblasts were incubated for 24 h with either vehicle control (0), 50 μM benzamidine hydrochloride (+B), 50 μg/ml leupeptin (+L), different concentrations of trypsin (10 or 50 ng/ml), 50 ng/ml trypsin and 50 μM benzamidine hydrochloride (50 +B), or 50 ng/ml trypsin and 50 μg/ml leupeptin (50 +L). [3H]Thymidine uptake during the last 12 h of culture was measured as an index of DNA synthesis. *, P < 0.05, significant difference between untreated fibroblasts and trypsin-treated fibroblasts. Values are mean ± SD.

Effects of Tryptase on ECM Protein Synthesis and COL I mRNA Level in Human Renal Fibroblasts

To clarify whether tryptase regulates ECM protein synthesis by renal fibroblasts, we performed gelatin-absorption assays for FN and immunoprecipitation assays for COL I, using [35S]methionine-labeled renal fibroblasts. As shown in Figure 7, incubation of renal fibroblasts with tryptase and heparin for 24 h resulted in increased synthesis of FN and COL I, in a dose-dependent manner. The synthesis of FN and COL I by tryptase- and heparin-treated fibroblasts was approximately 1.9- and 2.3-fold greater, respectively, than that of control cells in response to tryptase at a dose of 2 nM. Incubation of fibroblasts with concentrations of heparin identical to those used to stabilize tryptase activity increased synthesis of COL I protein 1.6-fold, compared with control values (Figure 7). Furthermore, Northern blot analysis revealed that 24-h incubations with tryptase and heparin increased COL I mRNA levels in cultured renal fibroblasts, whereas heparin alone had no significant effect on COL I mRNA levels (Figure 8), suggesting that the increases in COL I protein levels induced by heparin may be attributable to post-translational events in heparin-treated fibroblasts (34).

               Figure 7.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 7.

Effects of tryptase on the synthesis of fibronectin (FN) and collagen type I (COL I) by renal fibroblasts. Renal fibroblasts treated for 24 h with either vehicle (Control), 1 U/ml heparin, or 1 U/ml heparin and tryptase were metabolically labeled with [35S]methionine during the last 18 h. Immunoprecipitation and gelatin-Sepharose absorption assays were performed using a rabbit antibody against human COL I and gelatin-Sepharose (for FN), respectively. Molecular weight markers are shown on the left.

               Figure 8.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 8.

Effects of tryptase on COL I mRNA levels in renal fibroblasts. Renal fibroblasts were treated for 24 h with either vehicle (Control), 1 U/ml heparin, or 1 U/ml heparin and tryptase. (A) Total RNA isolated from fibroblasts after treatment was analyzed by Northern blotting, using 32P-labeled cDNA for COL I and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glyceraldehyde-3-phosphate dehydrogenase mRNA expression was used for signal normalization. (B) The densitometric analysis findings, after correction for glyceraldehyde-3-phosphate dehydrogenase mRNA levels, are graphically presented. The sizes of the transcripts are shown on the left.

Discussion

We demonstrated here for the first time that mast cell tryptase may be involved in the development of renal interstitial fibrosis in various types of renal diseases, including acute or chronic TIN. In addition, we demonstrated that mast cell tryptase was not only a potential mitogen but also a stimulator of the synthesis of ECM proteins by human renal fibroblasts.

These findings from immunohistochemical assays demonstrated significant correlations between the degree of renal interstitial fibrosis and the number of infiltrating tryptase-positive mast cells, suggesting that mast cells play an important role in renal interstitial fibrotic processes regardless of the type of renal disease. These findings extended other studies that focused on the involvement of mast cells in tubulointerstitial injuries accompanied by GN, to determine the general role of mast cells in the development of tubulointerstitial fibrosis not only in GN but also in acute and chronic TIN (18,19,20). Of note, mast cells were mainly detected in fibrotic lesions of TIN, rather than in edematous areas. Furthermore, mast cells could not be detected in any damaged glomeruli examined. These findings strongly suggested that mast cells are unique contributors to the development of renal interstitial fibrosis. Activation of mast cells can usually be induced by multiple mechanisms, including IgE- and complement-mediated pathways. Stem cell factor (SCF) has also been identified as a differentiation, chemoattraction, and activation factor for mast cells in human subjects (35,36,37). Recently, Hogaboam et al. (38) reported that SCF was constitutively produced by pulmonary fibroblasts and could be induced by tumor necrosis factor-α, which is contained in mast cells. Therefore, it was suggested that activated renal interstitial fibroblasts produce SCF after injuries, to attract mast cells to injured sites.

Mast cells synthesize and secrete histamine, heparin, and various proteases and chemical mediators, such as prostaglandins, leukotrienes, and platelet-activating factors (39). Mast cell tryptase is a major protease and produces mitogenic effects on various types of cultured cells, such as smooth muscle cells and bronchial epithelial cells (16,17). Its mitogenic potential may be dependent on its proteolytic activity. The mechanism of the signaling event that mediates the fibrogenic effects of tryptase remains unclear. Like the thrombin receptor, proteinase-activated receptor-2 (PAR-2), a prototypic G protein-coupled receptor, was recently considered to be activated by proteolytic cleavage and synthetic peptides corresponding to the newly generated amino terminus after receptor cleavage (40). PAR-2 is activated by not only trypsin but also tryptase in vitro (33). Consistent with these findings, our [3H]thymidine uptake experiments demonstrated that mast cell tryptase and trypsin have mitogenic activity for human renal fibroblasts and that tryptase-mediated cellular activation requires a proteolytic event similar to thrombin-mediated signal transduction. The development of selective PAR-2 antagonists is necessary for determination of the precise mechanisms by which tryptase induces mitogenic responses in renal fibroblasts.

It is interesting that heparin is required for induction of the full activity of tryptase in fibroblasts, because the effects of tryptase without heparin on fibroblast proliferation are less potent than those observed with heparin. Heparin is generally accepted to suppress cell proliferation in vivo and in vitro (41,42). Floege et al. (43) demonstrated that heparin suppressed mesangial cell proliferation and matrix expansion in experimental GN in rats. Castellot et al. (44) reported that heparin inhibited mitogenesis of cultured rat mesangial cells. The findings presented here also demonstrated that heparin suppressed proliferation of renal fibroblasts in vitro. Tryptase was recently demonstrated to be stabilized as an enzymatically active tetramer by association with heparin and dissociated to inactive monomers in the absence of heparin, suggesting that heparin is an essential component for the induction of tryptase action on cultured renal fibroblasts (11).

Mast cells are a major source of basic fibroblast growth factor (bFGF) in chronic inflammation (45). bFGF is mitogenic for a variety of cell types, including fibroblasts, smooth muscle cells, and endothelial cells, and is known to play an important role in wound healing and fibrosis (46). Ehara and Shigematu (19) suggested that mast cell-derived bFGF may be a key mediator in renal fibrosis. In addition, it was demonstrated that bFGF had very robust proliferative effects on renal interstitial fibroblasts, without significant effects on matrix synthesis (47). bFGF seems to be an important factor, similar to tryptase, in the development of renal fibrosis.

ECM protein deposition in the interstitium is a very important step leading to renal interstitial fibrosis. ECM deposition occurs when the balance between matrix synthesis and degradation is disturbed (48). Our findings indicated that tryptase, when coincubated with heparin, stimulated FN and COL I protein synthesis by renal fibroblasts. The increased COL I protein synthesis seemed to result from the increased COL I mRNA levels induced by tryptase. The amounts of both FN and COL I were demonstrated to increase in interstitial fibrosis of the kidney (49). Because tryptase does not alter matrix metalloproteinase expression in human dermal fibroblasts (50), this study strongly indicates that tryptase is a fibrogenic factor. Interestingly, heparin itself stimulated COL I protein synthesis but did not affect COL I mRNA expression in these experiments. This response may be attributable to the inhibitory effect of heparin on gene expression of matrix metalloproteinase-degrading ECM proteins (34).

Although it is possible that SV40-transformed human renal fibroblasts may have increased proliferative capacity, compared with primary fibroblasts, we think that our cell lines were suitable for these experiments, because our transformed fibroblasts maintained the same characteristics and produced the same ECM proteins as their primary counterparts (24).

In conclusion, we presented data indicating that mast cell tryptase may play a role in the proliferation of and ECM protein production in renal interstitial fibroblasts and may thus contribute to the development of renal interstitial fibrosis. These findings also indicated that the proteolytic activity of tryptase may be involved in the fibrogenic action of renal interstitial fibroblasts. Further studies using either administration of a neutralizing antibody against tryptase or application of a mast cell tryptase-knockout mouse strategy in experimental models of kidney fibrosis are required for more definitive determination of the role of tryptase in the development of kidney scarring.

Acknowledgments

We are grateful to Dr. Tetsuro Ogino and Dr. Akira Numata (Takamatsu Red Cross Hospital) for support in the immunohisto-chemical studies. We thank Dr. Kentaro Sakai (Tokushima University) and Dr. Hirokazu Okada (Saitama Medical College) for helpful discussions. Part of this work was presented in abstract form at the annual meeting of the American Society of Nephrology, November 1 to 8, 1999. This work was supported by a grant from the Japanese Ministry of Health and Welfare (Grant 12670756).

  • © 2001 American Society of Nephrology

References

  1. ↵
    Cameron JS: Tubular and interstitial factors in the progression of glomerulonephritis. Pediatr Nephrol6 : 292-303,1992
    OpenUrlCrossRefPubMed
  2. ↵
    Nath KA: Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis20 : 1-17,1992
    OpenUrlCrossRefPubMed
  3. ↵
    Eddy AA: Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 7:2495 -2508, 1996
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Wiggins R, Goyal M, Merritt S, Killen PD: Vascular adventitial cell expression of collagen I messenger ribonucleic acid in anti-glomerular basement membrane antibody-induced crescentic nephritis in the rabbit. Lab Invest 68:557 -565, 1993
    OpenUrlPubMed
  5. ↵
    Strutz F: Novel aspects of renal fibrogenesis. Nephrol Dial Transplant 10:1526 -1532, 1995
    OpenUrlPubMed
  6. ↵
    Kawanami O, Ferrans VJ, Fulmer JD, Crystal RG: Ultrastructure of pulmonary mast cells in patients with fibrotic lung disorders. Lab Invest 40:717 -734, 1979
    OpenUrlPubMed
  7. ↵
    Trabucchi E, Radaelli E, Marazzi M, Foschi D, Musazzi M, Veronesi AM, Montorsi W: The role of mast cells in wound healing. Int J Tissue React 10:367 -372, 1988
    OpenUrlPubMed
  8. ↵
    LeRoy EC, Smith EA, Kahaleh MB, Trojanowska M, Silver RM: A strategy for determining the pathogenesis of systemic sclerosis: Is transforming growth factor β the answer? Arthritis Rheum 32:817 -825, 1989
    OpenUrlPubMed
  9. ↵
    Claman HN: On scleroderma: Mast cells, endothelial cells and fibroblasts. J Am Med Assoc262 : 1206-1209,1989
    OpenUrlCrossRefPubMed
  10. ↵
    Schwartz LB: Tryptase from human mast cells: Biochemistry, biology, and clinical utility. In: Neutral Proteases of Mast Cells, edited by Schwartz LB, Basel, Karger, 1986, pp 90-113
  11. ↵
    Schwartz LB, Bradford TR: Regulation of tryptase from human lung mast cells by heparin: Stabilization of the active tetramer. J Biol Chem 261:7372 -7379, 1986
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Schwartz LB, Bradford TR, Littman BH, Wintroub BU: The fibrinogenolytic activity of purified tryptase from human lung mast cells. J Immunol 135:2762 -2767, 1985
    OpenUrlAbstract
  13. ↵
    Sekizawa K, Caughey GH, Lazarus SC, Gold WM, Nadel JA: Mast cell tryptase causes airway smooth muscle hyperresponsiveness in dogs. J Clin Invest 83:175 -179, 1989
    OpenUrlCrossRefPubMed
  14. ↵
    Caughey G, Leidig F, Viro N, Nadel JA: Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J Pharmacol Exp Ther 244:133 -137, 1988
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Ruoss SJ, Hartman T, Caughey GH: Mast cell tryptase is a mitogen for cultured fibroblasts. J Clin Invest88 : 493-499,1991
    OpenUrlCrossRefPubMed
  16. ↵
    Brown JK, Tyler CL, Jones CA, Ruoss SJ, Hartmann T, Caughey GH: Tryptase, the dominant secretary granular protein in human mast cells, is a potent mitogen for cultured dog tracheal smooth muscle cells. Am J Respir Cell Mol Biol 13:227 -236, 1995
    OpenUrlCrossRefPubMed
  17. ↵
    Cairns JA, Walls AF: Mast cell tryptase is a mitogen for epithelial cells: Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol 156:257 -283, 1996
    OpenUrl
  18. ↵
    Toho T, Toth-Jakatics R, Jimi S, Ihara M, Urata H, Takebayashi S: Mast cells in rapidly progressive glomerulonephritis. J Am Soc Nephrol 10:1498 -1505, 1999
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Ehara T, Shigematu H: Contribution of mast cells to the tubulo-interstitial lesions in IgA nephritis. Kidney Int 54:1675 -1683, 1998
    OpenUrlCrossRefPubMed
  20. ↵
    Hiromura K, Kurosawa M, Yano S, Naruse T: Tubulointerstitial mast cell infiltration in glomerulonephritis. Am J Kidney Dis 32: 593-599,1998
    OpenUrlPubMed
  21. ↵
    Combs HL, Shankland SJ, Setzer SV, Hudkins KL, Alpers CE: Expression of the cyclin kinase inhibitor p27kip1, in developing and mature human kidney. Kidney Int53 : 892-896,1998
    OpenUrlCrossRefPubMed
  22. ↵
    Lonnemann G, Shapiro L, Engler-Blum G, Müller GA, Koch KM, Dinarello CA: Cytokines in human renal interstitial fibrosis. I. Interleukin-1 is a paracrine growth factor for cultured fibrosis-derived kidney fibroblasts. Kidney Int 47: 837-844,1995
    OpenUrlCrossRefPubMed
  23. ↵
    Mulligan RC, Berg P: Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribo-syltransferase. Proc Natl Acad Sci USA78 : 2072-2076,1981
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Müller GA, Frank J, Rodemann HP, Engler-Blum G: Human renal fibroblast cell lines (tFKIF and tNKF) are new tools to investigate pathophysiologic mechanisms of renal interstitial fibrosis. Exp Nephrol 3:127 -133, 1995
    OpenUrlPubMed
  25. ↵
    Clayton A, Steadman R, Williams JD: Cells isolated from the human cortical interstitium resemble myofibroblasts and bind neutrophils in an ICAM-1-dependent manner. J Am Soc Nephrol4 : 604-615,1997
    OpenUrl
  26. ↵
    Abe M, Kurosawa M, Ishikawa O, Miyachi Y, Kido H: Mast cell tryptase stimulates both human dermal fibroblast proliferation and type I collagen production. Clin Exp Allergy28 : 1509-1517,1998
    OpenUrlCrossRefPubMed
  27. ↵
    Kagami S, Kondo S, Löster K, Reutter W, Urushihara M, Kitamura A, Kobayashi S, Kuroda Y: Collagen type I modulates the platelet-derived growth factor (PDGF) regulation of the growth and expression of β1 integrins by rat mesangial cells. Biochem Biophys Res Commun 252:728 -732, 1998
    OpenUrlCrossRefPubMed
  28. ↵
    Akers LA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ: Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am J Physiol278 : L193-L201,2000
    OpenUrlCrossRefPubMed
  29. ↵
    Kagami S, Border WA, Miller DE, Noble NA: Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-β expression in rat glomerular mesangial cells. J Clin Invest 93:2431 -2437, 1994
    OpenUrlCrossRefPubMed
  30. ↵
    Kagami S, Kuhara T, Yasutomo K, Okada K, Löster K, Reutter W, Kuroda Y: Transforming growth factor-β stimulates the expression of β1 integrins and adhesion by rat mesangial cells. Exp Cell Res229 : 1-6,1996
    OpenUrlCrossRefPubMed
  31. ↵
    Ignotz RA, Massague J: Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem261 : 4337-4345,1986
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Ricupero DA, Romero JR, Rishikof DC, Goldstein RH: Des-Arg 10-kallidin engagement of the B1 receptor stimulates type I collagen synthesis via stabilization of connective tissue growth factor mRNA. J Biol Chem 275:12475 -12480, 2000
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Mirza H, Schmidt VA, Derian CK, Jesty J, Bahou WF: Mitogenic responses mediated through the proteinase-activated receptor-2 are induced by expressed forms of mast cell α- and β-tryptases. Blood 90:3914 -3922, 1997
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Kitamura M, Maruyama N, Mitarai T, Nagasawa R, Yokoo T, Sakai O: Heparin selectively inhibits gene expression of matrix metalloproteinase transin in cultured mesangial cells. Biochem Biophys Res Commun 203:1333 -1338, 1994
    OpenUrlCrossRefPubMed
  35. ↵
    Valent P, Spanblochl E, Sperr WR, Sillaber C, Zsebo KM, Agis H, Strobl H, Geissler K, Bettelheim P, Lechner K: Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood 80:2237 -2245, 1992
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Nilsson G, Butterfield JH, Nilsson K, Siegbahn A: Stem cell factor is a chemotactic factor for human mast cells. J Immunol 153:3717 -3723, 1994
    OpenUrlAbstract
  37. ↵
    Columbo M, Horowitz EM, Botana LM, McGlashan DW Jr, Bochner BS, Gillis S, Zsebo KM, Galli SJ, Lichtenstein LM: The human recombinant c-kit receptor ligand, rhSCF, induces mediator release from human cutaneous mast cells and enhances IgE-dependent mediator release from both skin mast cells and peripheral blood basophils. J Immunol149 : 599-608,1992
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Hogaboam C, Kunkel SL, Strieter RM, Taub DD, Lincoln P, Strandiford TJ, Lukacs NW: Novel role of transmembrane SCF for mast cell activation and eotaxin production in mast cell-fibroblast interactions. J Immunol 160:6166 -6171, 1998
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Galli SJ: New concepts about the mast cell. N Engl J Med 328: 257-265,1993
    OpenUrlCrossRefPubMed
  40. ↵
    Dery O, Corvera CU, Steinhoff M, Bunnett NW: Proteinase-activated receptors: Novel mechanisms of signaling by serine proteases. Am J Physiol 274:C1429 -C1452, 1998
    OpenUrlPubMed
  41. ↵
    Clowes AW, Karnowsky MJ: Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature (Lond)265 : 625-626,1977
    OpenUrlCrossRefPubMed
  42. ↵
    Desmouliere A, Rubbia-Brandt L, Grau G, Gabbiani G: Heparin induces α-smooth muscle actin expression in cultured fibroblasts and in granulation tissue myofibroblasts. Lab Invest67 : 716-726,1992
    OpenUrlPubMed
  43. ↵
    Floege J, Eng E, Young BA, Couser WG, Johnson RJ: Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative glomerulonephritis. Kidney Int43 : 369-380,1993
    OpenUrlCrossRefPubMed
  44. ↵
    Castellot JJ Jr, Hoover RL, Karnovsky MJ: Glomerular endothelial cells secrete a heparin-like inhibitor and a peptide stimulator of mesangial cell proliferation. Am J Pathol125 : 493-500,1986
    OpenUrlPubMed
  45. ↵
    Qu Z, Liebler JM, Powers MR, Galey T, Ahmadi P, Huang XN, Ansel JC, Butterfield JH, Planck SR, Rosenbaum JT: Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol 147:564 -573, 1995
    OpenUrlPubMed
  46. ↵
    Klagsbrun M, Edelman ER: Biological and biochemical properties of fibroblast growth factors: Implications for the pathogenesis of atherosclerosis. Arteriosclerosis9 : 269-278,1989
    OpenUrlFREE Full Text
  47. ↵
    Strutz F, Zeisberg M, Hemmerlein B, Sattler B, Hummel K, Becker V, Muller GA: Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int 57:1521 -1538, 2000
    OpenUrlCrossRefPubMed
  48. ↵
    Strutz F, Müller GA: Renal fibrogenesis and progression. In: Immunologic Renal Diseases, edited by Neilson EG, Couser WG, Philadelphia, Lippincott-Raven Publishers, 1997, pp705 -726
  49. ↵
    Kuncio GS, Neilson EG, Haverty T: Mechanisms of tubulointerstitial fibrosis. Kidney Int 39:550 -556, 1991
    OpenUrlCrossRefPubMed
  50. ↵
    Zhang J, Gruber BL, Marchese MJ, Zucker S, Schwartz LB, Kew RR: Mast cell tryptase does not alter matrix metalloproteinase expression in human dermal fibroblasts: Further evidence that proteolytically-active tryptase is a potent fibrogenic factor. J Cell Physiol181 : 312-318,1999
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 12 (8)
Journal of the American Society of Nephrology
Vol. 12, Issue 8
1 Aug 2001
  • Table of Contents
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Role of Mast Cell Tryptase in Renal Interstitial Fibrosis
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Role of Mast Cell Tryptase in Renal Interstitial Fibrosis
SHUJI KONDO, SHOJI KAGAMI, HIROSHI KIDO, FRANK STRUTZ, GERHARD A. MÜLLER, YASUHIRO KURODA
JASN Aug 2001, 12 (8) 1668-1676; DOI: 10.1681/ASN.V1281668

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Role of Mast Cell Tryptase in Renal Interstitial Fibrosis
SHUJI KONDO, SHOJI KAGAMI, HIROSHI KIDO, FRANK STRUTZ, GERHARD A. MÜLLER, YASUHIRO KURODA
JASN Aug 2001, 12 (8) 1668-1676; DOI: 10.1681/ASN.V1281668
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Myeloid CCR2 Promotes Atherosclerosis after AKI
  • The Parietal Epithelial Cell: A Key Player in the Pathogenesis of Focal Segmental Glomerulosclerosis in Thy-1.1 Transgenic Mice
  • Gene Therapy via Blockade of Monocyte Chemoattractant Protein-1 for Renal Fibrosis
Show more Immunology and Pathology

Cited By...

  • Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-{beta} Receptor Signaling Pathways Contributes to Renal Fibrosis
  • The Mast Cell Stabilizer Ketotifen Fumarate Lessens Contracture Severity and Myofibroblast Hyperplasia: A Study of a Rabbit Model of Posttraumatic Joint Contractures
  • Role of Mast Cells in Progressive Renal Diseases
  • Mast Cell-Mediated Remodeling and Fibrinolytic Activity Protect against Fatal Glomerulonephritis
  • Addition of the Antioxidant Probucol to Angiotensin II Type I Receptor Antagonist Arrests Progressive Mesangioproliferative Glomerulonephritis in the Rat
  • A Pathogenetic Role for Mast Cells in Experimental Crescentic Glomerulonephritis
  • Protease-Activated Receptor-2-Mediated Proliferation and Collagen Production of Rat Pancreatic Stellate Cells
  • Protease-Activated Receptor-2 Expression in IgA Nephropathy: A Potential Role in the Pathogenesis of Interstitial Fibrosis
  • Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness
  • Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPAR{gamma}: Possible relevance to human fibrotic disorders
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire