Thrombin stimulates synthesis of type IV collagen and tissue inhibitor of metalloproteinases-1 by cultured human mesangial cells

Citation
M. Kaizuka et al., Thrombin stimulates synthesis of type IV collagen and tissue inhibitor of metalloproteinases-1 by cultured human mesangial cells, J AM S NEPH, 10(7), 1999, pp. 1516-1523
Citations number
59
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Urology & Nephrology","da verificare
Journal title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN journal
1046-6673 → ACNP
Volume
10
Issue
7
Year of publication
1999
Pages
1516 - 1523
Database
ISI
SICI code
1046-6673(199907)10:7<1516:TSSOTI>2.0.ZU;2-J
Abstract
Glomerular accumulation of extracellular matrix (ECM) is the common patholo gic feature following glomerular injury, and the alteration in the synthesi s and degradation of ECM may be involved in the glomerular accumulation of ECM. Glomerular fibrin formation occurs in various forms of human and exper imental glomerulonephritis, and it may play an important role in progressiv e glomerular injury. Thrombin, a multifunctional serine proteinase that is generated at the site of vascular injury, has central functions in hemostas is and it also shows various biologic effects. In this study, it is hypothe sized that thrombin may alter the production and the degradation of type IV collagen, which is an important component of ECM in the glomeruli. Human m esangial cells (HMC) were cultured, and the levels of type IV collagen, tis sue inhibitor of metalloproteinase-l (TIMP-1), and matrix metalloproteinase -2 (MMP-2) in the culture supernatants were measured by enzyme immunoassay using specific antibodies. MMP-2 activity was also evaluated by zymography using polyacrylamide/ sodium dodecyl sulfate gel-containing gelatin. Thromb in increased the production of type IV collagen and TIMP-1 in a dose- and t ime-dependent manner, but it did not increase MMP-2. Thrombin also stimulat ed the gene expressions of the type TV collagen and TIMP-1 in HMC in a dose - and time-dependent manner. Thrombin treated with diisopropylfluorophospha te, a serine proteinase inhibitor, did not show any of these effects. Hirud in, a natural thrombin inhibitor, and anti-transforming growth factor-beta- neutralizing antibody inhibited the stimulating effect of thrombin. These f indings suggest that thrombin may contribute to the excessive accumulation of ECM and progression of glomerulosclerosis through an increase of type IV collagen production and a decreased matrix degradation presumably via a tr ansforming growth factor-beta-dependent mechanism.