Role of mast cell tryptase in renal interstitial fibrosis

Renal interstitial fibrosis is characterized by increased proliferation of fibroblasts and excessive accumulation of extracellular matrix. Mast cell t ryptase has been implicated in the development of tissue fibrosis in skin a nd lungs. However, the significance of mast cell tryptase in human renal di seases has not been investigated. The potential role of mast cell-derived t ryptase in the development of renal fibrosis was studied using immunohistoc hemical techniques and cultured human renal fibroblast cell lines. Semiquan titative immunostaining analysis of samples from 70 patients with several r enal 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 infil trating tryptase-positive mast cells (P < 0.01). Mast cells could not be de tected in damaged glomeruli in any form of renal disease. [H-3]Thymidine up take experiments demonstrated that DNA synthesis by cultured renal fibrobla sts was increased with the concentration of tryptase (0.5 to 5 nM) coincuba ted with heparin and was suppressed by coincubation with the protease inhib itors leupeptin and benzamidine hydrochloride. Tryptase alone also increase d DNA synthesis by fibroblasts but exhibited less effectiveness, compared w ith the combination of tryptase and heparin. Conversely, heparin alone supp ressed DNA synthesis by fibroblasts. Metabolic [S-35]methionine-labeling ex periments with cultured renal fibroblasts indicated that tryptase increased the synthesis of fibronectin and collagen type I, in a dose-dependent mann er. These findings suggest that mast cell tryptase plays a role in the prol iferation and extracellular matrix protein production of renal interstitial fibroblasts and thus contributes to the development of renal interstitial fibrosis.