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.
Elliot
S J
SJ
Renal Cell Biology Section, Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Striker
L J
LJ
Stetler-Stevenson
W G
WG
Jacot
T A
TA
Striker
G E
GE
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects*; D018093:Gelatinases / Q000032:analysis; D005920:Glomerular Mesangium / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis
D019714:Tissue Inhibitor of Metalloproteinases; D010426:Pentosan Sulfuric Polyester; D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2