Glomerular matrix accumulation is linked to inhibition of the plasmin protease system

Suguru Tomooka, Wayne A. Border, Bruce C. Marshall, Nancy A. Noble

Research output: Contribution to journalArticlepeer-review

Abstract

TGF-β plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-β expression leads to increased synthesis and deposition of extracellular matrix components while administration of antiserum to TGF-β suppresses the major manifestations of the disease. We hypothesized that TGF-β might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-β was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-β serum to giomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-β in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-β production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-β enhances the matrix accumulation characteristic of many glomerular diseases.

Original languageEnglish (US)
Pages (from-to)1462-1469
Number of pages8
JournalKidney international
Volume42
Issue number6
DOIs
StatePublished - Dec 1992

ASJC Scopus subject areas

  • Nephrology

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