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

Glomerulosclerosis is characterized by extracellular matrix accumulation an d is often associated with mesangial cell proliferation. Heparin-like molec ules have been shown to decrease glomerulosclerosis in vivo, although their cellular site and mechanism of action is still unclear. In this study, a l ine of glomerular mesangial cells derived from normal mice was used to dete rmine whether pentosan polysulfate (PPS) inhibited proliferation and altere d extracellular matrix turnover. Cells treated with PPS showed a decrease i n 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 immuno sorbent assay as well as matrix metalloproteinases (MMP) measured by zymogr aphy. Collagen types I and type IV were significantly decreased in the medi a (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 increa sed after treatment with PPS (P < 0.001) and heparin (P < 0.05). PPS and he parin also decreased MMP-9 (P < 0.001) after treatment. Reverse zymography showed the presence of tissue inhibitors of metal-loproteinases (TIMP)-1and -2 in control mesangial cells. Treatment with PPS and heparin increased TI MP-1, Zn addition, TIMP-3 was found in the medium of treated but not contro l cells. In conclusion, PPS alters extracellular matrix turnover through th e induction of MMP-2 and alterations in the TIMP profile and may be useful in decreasing progressive glomerulosclerosis.