Pentosan polysulfate decreases proliferation and net extracellular matrix production in mouse mesangial cells

Glomerulosclerosis is characterized by extracellular matrix accumulation and is often associated with mesangial cell proliferation. Heparin-like molecules have been shown to decrease glomerulosclerosis in vivo, although their cellular site and mechanism of action is still unclear. In this study, a line of glomerular mesangial cells derived from normal mice was used to determine whether pentosan polysulfate (PPS) inhibited proliferation and altered extracellular matrix turnover. Cells treated with PPS showed a decrease in cell number beginning 24 h after treatment, which was maintained for 5 d. For matrix accumulation and degradation studies, cells were treated for 5 d and collagen types I and IV protein were measured by enzyme-linked immunosorbent assay as well as matrix metalloproteinases (MMP) measured by zymography. Collagen types 1 and type IV were significantly decreased in the media (P < 0.0001) and cell layer (P < 0.005) after treatment with PPS but not after treatment with heparin. By zymography, MMP-2 was significantly increased after treatment with PPS (P < 0.001) and heparin (P < 0.05). PPS and heparin also decreased MMP-9 (P < 0.001) after treatment. Reverse zymography showed the presence of tissue inhibitors of metalloproteinases (TIMP)-1 and -2 in control mesangial cells. Treatment with PPS and heparin increased TIMP-1. In addition, TIMP-3 was found in the medium of treated but not control cells. In conclusion, PPS alters extracellular matrix turnover through the induction of MMP-2 and alterations in the TIMP profile and may be useful in decreasing progressive glomerulosclerosis.