Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis.
Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. The progression of renal lesions to fibrosis involves several mechanisms, among which the inhibition of extracellular matrix (ECM) degradation appears to play an important role. Two interrelated proteolytic systems are involved 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 expressed in the normal human kidney but is strongly induced in various forms of kidney diseases, leading to renal fibrosis and terminal renal failure. Thrombin, angiotensin II, and transforming growth factor-beta are potent in vitro and in vivo agonists in increasing PAI-1 synthesis. Several experimental and clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis, diabetic nephropathy, focal segmental glomerulosclerosis, and other fibrotic renal diseases. Experimental models of renal diseases in PAI-1-deficient animals are in progress, and preliminary results indicate a role for PAI-1 in renal fibrogenesis. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic antagonists, 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.
Rerolle
J P
JP
INSERM U489, Hôpital Tenon, Paris, France.
Hertig
A
A
Nguyen
G
G
Sraer
J D
JD
Rondeau
E P
EP
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D015854:Up-Regulation
D017395:Plasminogen Activator Inhibitor 1; D008666:Metalloendopeptidases