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Thrombin Stimulates Synthesis of Type IV Collagen and Tissue Inhibitor of Metalloproteinases-1 by Cultured Human Mesangial Cells

MITSUAKI KAIZUKA^*, HIDEAKI YAMABE^*, HIROSHI OSAWA^*, KEN OKUMURA^* and NOBORU FUJIMOTO

^* Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.
Biopharmaceutical Department, Research Institute, Fuji Chemical Industries, Ltd., Takaoka, Japan.

Correspondence to Dr. Hideaki Yamabe, Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036, Japan. Phone: 81 172 395057; Fax: 81 172 359190; E-mail: yamabe{at}cc.hirosaki-u.ac.jp .

Abstract. Glomerular accumulation of extracellular matrix (ECM) is the common pathologic feature following glomerular injury, and the alteration in the synthesis and degradation of ECM may be involved in the glomerular accumulation of ECM. Glomerular fibrin formation occurs in various forms of human and experimental glomerulonephritis, and it may play an important role in progressive glomerular injury. Thrombin, a multifunctional serine proteinase that is generated at the site of vascular injury, has central functions in hemostasis and it also shows various biologic effects. In this study, it is hypothesized that thrombin may alter the production and the degradation of type IV collagen, which is an important component of ECM in the glomeruli. Human mesangial cells (HMC) were cultured, and the levels of type IV collagen, tissue inhibitor of metalloproteinase-1 (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. Thrombin increased the production of type IV collagen and TIMP-1 in a dose- and time-dependent manner, but it did not increase MMP-2. Thrombin also stimulated the gene expressions of the type IV collagen and TIMP-1 in HMC in a dose- and time-dependent manner. Thrombin treated with diisopropylfluorophosphate, a serine proteinase inhibitor, did not show any of these effects. Hirudin, a natural thrombin inhibitor, and anti-transforming growth factor-ß-neutralizing antibody inhibited the stimulating effect of thrombin. These findings 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 transforming growth factor-ß-dependent mechanism.

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