Role of mast cells, stem cell factor and protease-activated receptor-2 in tubulointerstitial lesions in IgA nephropathy
- 279 Downloads
To elucidate the role of mast cells (MCs) in the pathogenesis of tubulointerstitial lesions in IgA nephropathy (IgAN), we investigated the number of MCs, serum stem cell factor (SCF), protease-activated receptor-2 (PAR-2) and α-smooth-muscle actin (α-SMA) in the kidney and the correlation between MC number, SCF, PAR-2, α-SMA and tubulointerstitial lesions in biopsy specimens and serum creatinine levels, urinary protein excretion in patients with IgA nephropathy.
Thirty-five patients with IgA nephropathy were enrolled in this study. Clinical parameters, such as serum creatinine and urinary protein excretion, were obtained from each patient at the time of biopsy. Paraffin-embedded sections were used for immunohistochemical staining. Monoclonal antibodies to human tryptase, α-SMA, and SCF and polyclonal antibody to PAR-2 were used as primary antibodies. Ten cortical interstitial fields were randomly selected and assessed using a computer-assisted color image analyzer. Tubulointerstitial fibrosis was assessed as the percentage of the area stained with Masson trichrome in ten cortical interstitial fields.
In all of the control subjects, few tryptase-positive MCs were observed in the glomeruli and interstitium. In contrast, sparse MCs were observed in the interstitium, but not in the glomeruli of diseased kidneys. The number of interstitial MCs in the tubulointerstitial lesions, the expression of SCF, PAR-2 and α-SMA were positively correlated with the degree of interstitial fibrosis. A close correlation between MCs, α-SMA, PAR-2 and SCF was found (r = 0.887 for α-SMA, r = 0.844 for PAR-2, r = 0.853 for SCF, P < 0.01). Also a close correlation between α-SMA, PAR-2 and SCF was found (r = 0.874 for PAR-2, r = 0.862 for SCF, P < 0.01). PAR-2 was correlated with SCF (r = 0.893, P < 0.01). Moreover, a significant positive correlation was observed between the number of interstitial MCs, the expression of SCF, PAR-2 and α-SMA and the serum creatinine level (r = 0.738 for MCs, r = 0.658 for α-SMA, r = 0.692 for PAR-2, r = 0.754 for SCF, P < 0.05).
Our findings suggest that MC infiltration possibly induced by SCF in renal interstitial tissues seems to be associated with tubulointerstitial fibrosis through PAR-2 in IgA nephropathy.
KeywordsIgA nephropathy Mast cells Stem cell factor Protease-activated receptor-2 Tubulointerstitial fibrosis
- 1.Berger J, Hinglais N. Intercapillary deposits of IgA–IgG. J Urol Nephrol (Paris). 1968;74:694–5.Google Scholar
- 10.Bohle A, Muller GA, Wehrmann M, et al. Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies and chronic interstitial nephritides. Kidney Int. 1996;49:S2–9.Google Scholar
- 13.Schulman ES. The role of mast cells in inflammatory reponses in the lung. Crit Rev Immunol. 131:35–70.Google Scholar
- 14.Craig SS, Deblois G, Schwartz LB. Mast cells in human keloid, small intestine, and lung by an immunoperoxidase technique using a murine monoclonal antibody against tryptase. Am J Pathol. 1986;124:428–35.Google Scholar
- 22.Nilsson G, Butterfield JH, Nilsson K, Siegbaha A. Stem cell factor is chemotactic for human mast cells. J Immunol. 1994;1533:3718–23.Google Scholar
- 26.Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, et al. Am J Physiol. 2000;278:L193–201.Google Scholar
- 31.Kawabata A. PAR-2: structure, function and relevance to human diseases of the gastric mucosa. Expert Rev Mol Med. 2002;16:1–17.Google Scholar
- 42.Columbo M, Horowitz EM, Botana LM, McGlashan DW Jr, Bochner BS, Gillis S, et al. 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 Immunol. 1992;149:599–608.PubMedGoogle Scholar
- 47.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. 1996;156:257–83.Google Scholar