Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.
TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta 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-beta 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-beta serum to glomerulonephritic 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-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.
Tomooka
S
S
Division of University of Utah School of Medicine, Salt Lake City.
Border
W A
WA
Marshall
B C
BC
Noble
N A
NA
D000818:Animals; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005921:Glomerulonephritis / Q000209:etiology / Q000378:metabolism; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D010960:Plasminogen Activators / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
D017395:Plasminogen Activator Inhibitor 1; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D010960:Plasminogen Activators