Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis

The progression of renal lesions to fibrosis involves several mechanisms, a mong which the inhibition of extracellular matrix (ECM) degradation appears to play an important role. Two interrelated proteolytic systems are involv ed in matrix degradation: the plasminogen activation system and the matrix metalloproteinase system. The plasminogen activator inhibitor type 1 (PAI-1 ), as the main inhibitor of plasminogen activation, regulates fibrinolysis and the plasmin-mediated matrix metalloproteinase activation. PAI-1 is also a component of the ECM, where it binds to vitronectin. PAI-1 is not expres sed in the normal human kidney but is strongly induced in various forms of kidney diseases, leading to renal fibrosis and terminal renal failure. Thro mbin, angiotensin II, and transforming growth factor-p are potent in vitro and in vivo agonists in increasing PAI-1 synthesis. Several experimental an d clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis, diabetic nephropathy, focal segme ntal glomerulosclerosis, and other fibrotic renal diseases. Experimental mo dels of renal diseases in PAI-l-deficient animals are in progress, and prel iminary results indicate a role for PAI-1 in renal fibrogenesis. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic a ntagonists, antisense oligonucleotides, or decoy oligonucleotides has been obtained in vitro, but needs to be evaluated in vivo for the prevention or the treatment of renal fibrosis.