Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis
Authors: Jean-Philippe Rerolle, Alexandre Hertig, Genevieve Nguyen, Jean-Daniel Sraer, Eric P. Rondeau
Journal: Kidney International (2000)

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-β 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. 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-β 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. The hallmark of terminal renal failure is the irreversible destruction of the normal renal parenchyma, more or less rapidly invaded and replaced by fibrosis. To date, although numerous studies have been reported on the various factors that may promote, or conversely delay, the progression of chronic renal failure, we are still looking for an integrated and unifying understanding of the molecular and cellular mechanisms implicated in the renal fibrogenic process. Fibrosis is due to the abnormal accumulation of extracellular matrix (ECM) in basement membranes and interstitial tissues and is combined, at the same time, with the elimination of normal parenchymal cells by necrosis, lack of regeneration, and/or apoptosis1Eddy A.A. Molecular insights into interstitial fibrosis.J Am Soc Nephrol. 1996; 7: 2495-2508Crossref PubMed Google Scholar. The abnormal ECM in fibrosis is made of an excess of normal components of ECM such as fibronectin, laminin, proteoglycans, and collagen type IV, but also of an accumulation of proteins that is not found in the normal ECM such as collagen type I and type III in the glomerular mesangium2Fogo A.B. Mesangial matrix modulation and glomerulosclerosis.Exp Nephrol. 1999; 7: 147-159Crossref PubMed Scopus (93) Google Scholar. These latter proteins characterize the scarring process and are usually irreversibly deposited in the fibrotic tissues. The renal parenchymal cells themselves may undergo a fibroblastic transdifferentiation and overproduce the ECM components. Fibroblasts and myofibroblasts proliferating within the kidney are also involved in the fibrogenic process. On the other hand, the ECM can be degraded, and it is likely that the fibrogenic process may also result from a deficit in ECM degradation. However, the relationship between ECM degradation and fibrogenesis is more complex than initially suspected, since abnormal ECM accumulation is often preceded or combined with an increased expression of ECM-degrading enzymes3Stetler-Stevenson W.G. Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix.Am J Pathol. 1996; 148: 1345-1350PubMed Google Scholar. This increased proteolytic activity is presumably required for degradation of the normal ECM by infiltrating inflammatory and fibroblastic cells and its replacement by abnormal ECM. Two main degrading systems are known to play a role: the matrix metalloproteinases (MMPs) and the plasminogen activation system (PAS)4Rondeau E. Sraer J.D. Schleuning W.D. The renal plasminogen activating system.Molecular Nephrology: Kidney Function in Health and Diseases. Marcel Dekker Inc., New York1995: 699-715Google Scholar. The relationship between these systems is numerous and has been reviewed elsewhere recently5Eitzman D.T. Ginsburg D. Of mice and men: The function of plasminogen activator inhibitors (PAIs) in vivo.Adv Exp Med Biol. 1997; 425: 131-141Crossref PubMed Google Scholar, 6Carmeliet P. Collen D. Vascular development and disorders: Molecular analysis and pathogenic insights.Kidney Int. 1998; 53: 1519-1549Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 7Ye S. Humphries S. Henney A. Matrix metalloproteinases: Implication in vascular matrix remodelling during atherogenesis.Clin Sci. 1998; 94: 103-110Crossref PubMed Scopus (56) Google Scholar. The aim of the present review is to analyze the available experimental and clinical data supporting a role for the main inhibitor of plasminogen activation, the plasminogen activator inhibitor type 1 (PAI-1), as a key player in renal fibrogenesis. The plasminogen/plasmin system was first recognized for its fibrin-degrading activity and is the main, if not the only, efficient fibrinolytic system in vivo Figure 1. The limiting rate of plasmin generation is the amount of tissue-type (t-PA) or urokinase-type (u-PA) plasminogen activators (PAs) in their active forms4Rondeau E. Sraer J.D. Schleuning W.D. The renal plasminogen activating system.Molecular Nephrology: Kidney Function in Health and Diseases. Marcel Dekker Inc., New York1995: 699-715Google Scholar. This amount is tightly regulated through the control of the synthesis and release of the proenzyme forms of PA, the extracellular activation of these proenzymes, and their inhibition by specific inhibitors such as PAI-1, PAI-2, and PAI-35Eitzman D.T. Ginsburg D. Of mice and men: The function of plasminogen activator inhibitors (PAIs) in vivo.Adv Exp Med Biol. 1997; 425: 131-141Crossref PubMed Google Scholar. These inhibitors belong to the SERPIN family, after the SERine Protease INhibitor. PAI-1, a 50 kD glycoprotein, is the main PAI secreted in vivo and is a potent fast-acting and irreversible inhibitor of t-PA and u-PA but not of plasmin. It forms stochiometric complexes with active PAs, which are subsequently endocytozed and degraded. Membrane receptors for u-PA and t-PA have been identified that facilitate the activation of plasminogen at the cell surface and the activation of the PA proenzymes by trace amounts of plasmin8Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system.Thromb Haemost. 1999; 82: 298-304Crossref PubMed Scopus (171) Google Scholar. In addition, u-PA receptor (u-PAR) plays a role in binding and internalization of u-PA/PAI complexes and in cell adhesion and migration through an interaction with vitronectin and integrins8Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system.Thromb Haemost. 1999; 82: 298-304Crossref PubMed Scopus (171) Google Scholar. The other main extracellular proteolytic system, the MMPs and their inhibitors (TIMP-1, TIMP-2, and TIMP-3), exist in a number of different metalloproteinases that contain several conserved motifs and a zinc binding site, which is required for full enzymatic activity. To date, at least 20 MMPs have been identified that belong to four different groups according to their specificity: (1) the collagenases, which cleave preferentially interstitial collagens type I and III; (2) the gelatinases, which degrade the collagens type IV and V; (3) the stromelysins, which degrade gelatin, fibronectin, laminin, and elastin; and (4) the membrane-type MMPs (MT-MMPs)7Ye S. Humphries S. Henney A. Matrix metalloproteinases: Implication in vascular matrix remodelling during atherogenesis.Clin Sci. 1998; 94: 103-110Crossref PubMed Scopus (56) Google Scholar. The MMPs are secreted in the extracellular space in catalytically latent forms because of the binding of the active site zink atom to an unpaired cystein of the propeptide domain. Disruption of the cystein-zink bound by conformational change or by limited proteolysis, as produced by plasmin, leads to the opening of the switch. Then the autocatalytic cleavage of the propeptide yields the active enzyme7Ye S. Humphries S. Henney A. Matrix metalloproteinases: Implication in vascular matrix remodelling during atherogenesis.Clin Sci. 1998; 94: 103-110Crossref PubMed Scopus (56) Google Scholar. The activation of MMPs may also occur through the cleavage by membrane-bound MMPs, which are called MT-MMPs. The activation of MMP2 at the cell surface is due to MT1-MMP, which binds TIMP-2 and forms a ternary complex with MMP2. Active MMP2 is then released into the extracellular space, but may also remain at the cell surface, where it has been shown to bind to the integrin αvβ39Brooks P.C. Strömblad S. Sanders L.C. von Schalscha T.L. Aimes R.T. Stetler-Stevenson W.G. Quigley J.P. Cheresh D.A. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3.Cell. 1996; 85: 683-693Abstract Full Text Full Text PDF PubMed Scopus (1429) Google Scholar. Interestingly, in our laboratory, u-PA was shown to promote MMP2 activation when purified u-PA was added to the culture medium conditioned by human mesangial cells, but not when added to purified pro-MMP2. We were able to demonstrate that mesangial cells release a soluble form of MT1-MMP that was activated by u-PA and then was responsible for MMP2 activation10Kazes I. Delarue F. Hagège J. Bouzhir-Sima L. Rondeau E. Sraer J.D. Nguyen G. Soluble latent membrane-type 1 matrix metalloprotease secreted by human mesangial cells is activated by urokinase.Kidney Int. 1998; 54: 1976-1984Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar. PAI-1, as a potent inhibitor of u-PA, inhibits u-PA-induced, MT1-MMP–mediated MMP2 activation11Baricos W.H. Cortez S.L. El-Dahr S.S. Schnaper H.W. ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP-2 cascade.Kidney Int. 1995; 47: 1039-1047Abstract Full Text PDF PubMed Scopus (212) Google Scholar. Thus, PAI-1 regulates plasmin formation and fibrinolysis and, through several different mechanisms, plays a role in the control of MMP activation. Its role in matrix remodeling derives from these effects. Moreover, PAI-1 is also a component of the ECM, where it seems to bind tightly to the somatomedin B domain of vitronectin12Knudsen B.S. Harpel P.C. Nachman R.L. Plasminogen activator inhibitor is associated with the extracellular matrix of cultured bovine smooth muscle cells.J Clin Invest. 1978; 80: 1082-1089Crossref Scopus (112) Google Scholar. This interaction stabilizes PAI-1 in an active conformation, still able to inhibit extracellular PA activity, and thus plasmin formation and MMP activation. In addition, PAI-1 binding to vitronectin has been shown to disrupt the interaction between uPAR and vitronectin, preventing adhesion of the cell to the ECM. uPAR may bind u-PA and promote ECM degradation either directly by u-PA through the proteolytic cleavage of fibronectin, laminin, and other components or indirectly through plasmin generation and MMP activation8Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system.Thromb Haemost. 1999; 82: 298-304Crossref PubMed Scopus (171) Google Scholar. As a result, PAI-1 has been shown to promote cell migration at least in vitro13Waltz D.A. Natkin L.R. Fujita R.M. Wei Y. Chapman H.A. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectine.J Clin Invest. 1997; 100: 58-67Crossref PubMed Scopus (260) Google Scholar,14Stefansson S. Lawrence D.A. The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin.Nature. 1996; 383: 441-443Crossref PubMed Scopus (606) Google Scholar. The PAI-1 gene has been cloned and sequenced and contains at its 5′ regulatory end several known consensus cis regulatory elements, which bind transactivating factors such as Sp1, activated protein-1 (AP-1), nuclear factor-κB (NF-κB), Smad3 and Smad4, and others Figure 215Chen Y.Q. Su M. Walia R.R. Hao Q. Covington J.W. Vaughan D.E. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells.J Biol Chem. 1998; 273: 8225-8231Crossref PubMed Scopus (173) Google Scholar, 16Keeton M.R. Curriden S.A. van Zonneveld A.J. Loskutoff D.J. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta.J Biol Chem. 1991; 266: 23048-23052Abstract Full Text PDF PubMed Google Scholar, 17Dawson S.J. Wiman B. Hamsten A. Green F. Humphries S. Henney A.M. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells.J Biol Chem. 1993; 15: 10739-10745Google Scholar, 18Dennler S. Itoh S. Vivien D. ten Dijke P. Huet S. Gauthier J.M. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.EMBO J. 1998; 17: 3091-3100Crossref PubMed Scopus (1267) Google Scholar, 19van Zonneveld A.J. Curriden S.A. Loskutoff D.J. Type 1 plasminogen activator inhibitor gene: functional analysis and glucocorticoid regulation of its promoter.Proc Natl Acad Sci USA. 1988; 85: 5525-5529Crossref PubMed Scopus (191) Google Scholar. The PAI-1 gene transcription is activated in many different renal cell types by inflammatory cytokines, especially interleukin-1β (IL-1β)20Wilson H.M. Reid F.J. Brown P.A.J. Power D.A. Haites N.E. Booth N.A. Effect of transforming growth factor-β1 on plasminogen activators and plasminogen activator inhibitor-1 in renal glomerular cells.Exp Nephrol. 1993; 1: 343-350PubMed Google Scholar and tumor necrosis factor-α (TNF-α)21Meulders Q. He C.J. Adida C. Peraldi M.N. Schleuning W.D. Sraer J.D. Rondeau E. Tumor necrosis factor-α increases antifibrinolytic activity of cultured human mesangial cells.Kidney Int. 1992; 42: 327-334Abstract Full Text PDF PubMed Scopus (31) Google Scholar,22Kanalas J.J. Hopfer U. Effect of TGF-β1 and TNF-α on the plasminogen system of rat proximal tubular epithelial cells.J Am Soc Nephrol. 1997; 8: 184-192PubMed Google Scholar, and by transforming growth factor-β (TGF-β)20Wilson H.M. Reid F.J. Brown P.A.J. Power D.A. Haites N.E. Booth N.A. Effect of transforming growth factor-β1 on plasminogen activators and plasminogen activator inhibitor-1 in renal glomerular cells.Exp Nephrol. 1993; 1: 343-350PubMed Google Scholar,23Dennler H. Itoh S. Vivien D. Dijke P. Huet S. Gauthier J.M. Direct binding of Smad3 and Smad4 to critical TGFβ-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.EMBO J. 1998; 17: 3091-3100Crossref PubMed Scopus (1580) Google Scholar, glucocorticoids, and nonspecific protein kinase C (PKC) activators such as phorbol myristate acetate (PMA)24Peraldi M.N. Rondeau E. Medcalf R.L. Hagège J. Lacave R. Delarue F. Schleuning W.D. Sraer J.D. Cell-specific regulation of plasminogen activator inhibitor 1 and tissue type plasminogen activator release by human kidney mesangial cells.Biochim Biophys Acta. 1992; 1134: 189-196Crossref PubMed Scopus (19) Google Scholar. Many cell types have been shown to produce PAI-1, such as endothelial cells, smooth muscle cells, hepatocytes, fibroblasts, or inflammatory cells4Rondeau E. Sraer J.D. Schleuning W.D. The renal plasminogen activating system.Molecular Nephrology: Kidney Function in Health and Diseases. Marcel Dekker Inc., New York1995: 699-715Google Scholar,5Eitzman D.T. Ginsburg D. Of mice and men: The function of plasminogen activator inhibitors (PAIs) in vivo.Adv Exp Med Biol. 1997; 425: 131-141Crossref PubMed Google Scholar. Renal cells themselves also produce PAI-1 in culture conditions21Meulders Q. He C.J. Adida C. Peraldi M.N. Schleuning W.D. Sraer J.D. Rondeau E. Tumor necrosis factor-α increases antifibrinolytic activity of cultured human mesangial cells.Kidney Int. 1992; 42: 327-334Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 22Kanalas J.J. Hopfer U. Effect of TGF-β1 and TNF-α on the plasminogen system of rat proximal tubular epithelial cells.J Am Soc Nephrol. 1997; 8: 184-192PubMed Google Scholar, 23Dennler H. Itoh S. Vivien D. Dijke P. Huet S. Gauthier J.M. Direct binding of Smad3 and Smad4 to critical TGFβ-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.EMBO J. 1998; 17: 3091-3100Crossref PubMed Scopus (1580) Google Scholar and in vivo in pathological conditions Table 1. In physiological conditions, the main source of circulating PAI-1 is the platelets, where it is stored and released upon activation. Three different forms of circulating PAI-1 can be detected: an active free form representing up to 80% of total PAI-1, a latent inactive form, and a form complexed to t-PA. The plasma level of circulating PAI-1 has been shown to be genetically controlled, and a polymorphism in the 5′ gene promoter has been described. Two alleles, 4G and 5G, at position -674 in the promoter region, are encountered, and the plasma level of PAI-1 has been shown to be higher in patients with the 4G/4G genotype than in those with the 5G/5G genotype, while the heterozygotes 4G/5G have intermediate values40Dawson S.J. Wiman B. Hamsten A. Green F. Humphries S. Henney A.M. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells.J Biol Chem. 1993; 15: 10739-10745Google Scholar. The genotype determines not only the plasma level of PAI-1, but it has been shown also to be associated with an increased risk of myocardial infarction in adult male patients. The molecular mechanisms involved in the increased synthesis of PAI-1 by the 4G allele as compared with the 5G allele are related to the binding of NF-κB to the cis regulatory region -680 to -670, which is partially inhibited by a regulatory protein, binding to the 5G sequence but not, or to a lesser extent, to the 4G sequence. Under IL-1 stimulation of the cells, the PAI-1 gene transcription rate is higher with the 4G allele than with the 5G allele41Ericksson P. Kallin B. Van't Hooft F.M. Bavenholm P. Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction.Proc Natl Acad Sci USA. 1995; 92: 1851-1855Crossref Scopus (742) Google Scholar.Table 1Experimental and human kidney diseases in which plasminogen inhibitor type 1 (PAI-1) accumulation has been demonstratedType of diseaseHostReferenceI. Fibrin-associated nephropathies Crescentic glomerulonephritismanRondeau25Rondeau E. Mougenot B. Lacave R. Peraldi M.N. Kruithof E.K.O. Sraer J.D. plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies.Clin Nephrol. 1990; 33: 55-60PubMed Google ScholarratFeng26Feng L. Tang W.W. Loskutoff D.J. Wilson C.B. Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis.J Am Soc Nephrol. 1993; 3: 1753-1764PubMed Google ScholarrabbitMalliaros27Malliaros J. Holdsworth S.R. Wojta J. Erlich J. Tipping P.G. Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits.Kidney Int. 1993; 44: 557-564Abstract Full Text PDF PubMed Scopus (37) Google Scholar Thrombotic microangiopathymanRondeau25Rondeau E. Mougenot B. Lacave R. Peraldi M.N. Kruithof E.K.O. Sraer J.D. plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies.Clin Nephrol. 1990; 33: 55-60PubMed Google ScholarmanXu28Xu Y. Hagège J. Mougenot B. Sraer J.D. Rønne E. Rondeau E. Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney.Kidney Int. 1996; 50: 2011-2019Abstract Full Text PDF PubMed Scopus (70) Google Scholar Lupus nephritismouseMoll29Moll S. Menoud P.A. Fulpius T. Pastore Y. Takahashi S. Fossati L. Vassalli J.D. Sappino A.P. Schifferli J.A. Izui S. Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis.Kidney Int. 1995; 48: 1459-1468Abstract Full Text PDF PubMed Scopus (64) Google Scholar Mixed cryoglobulinemiamouseMoll29Moll S. Menoud P.A. Fulpius T. Pastore Y. Takahashi S. Fossati L. Vassalli J.D. Sappino A.P. Schifferli J.A. Izui S. Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis.Kidney Int. 1995; 48: 1459-1468Abstract Full Text PDF PubMed Scopus (64) Google Scholar EndotoxinemiamouseMoll29Moll S. Menoud P.A. Fulpius T. Pastore Y. Takahashi S. Fossati L. Vassalli J.D. Sappino A.P. Schifferli J.A. Izui S. Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis.Kidney Int. 1995; 48: 1459-1468Abstract Full Text PDF PubMed Scopus (64) Google ScholarmouseYamamoto30Yamamoto T. Loskutoff D.J. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator.J Clin Invest. 1996; 97: 2440-2451Crossref PubMed Scopus (181) Google Scholar Radiation nephropathyratOikawa31Oikawa T. Freeman M. Lo W. Vaughan D.E. Fogo A. Modulation of plasminogen activator inhibitor type-1 in vivo: A new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition.Kidney Int. 1997; 51: 164-172Abstract Full Text PDF PubMed Scopus (216) Google Scholar Acute renal graft rejectionmanWang32Wang Y. Pratt J.R. Hartley B. Evans B. Zhang L. Sacks S.H. Expression of tissue type plasminogen activator and type 1 plasminogen activator inhibitor, and persistent fibrin deposition in chronic renal allograft failure.Kidney Int. 1997; 52: 371-377Abstract Full Text PDF PubMed Scopus (47) Google ScholarII. Fibrin-free nephropathies Cobra venom nephritisratBarnes33Barnes J.L. Mitchell R.J. Torres E.S. Expression of plasminogen activator-inhibitor-1 (PAI-1) during cellular remodeling in proliferative glomerulonephritis in the rat.J Histochem Cytochem. 1995; 43: 895-905Crossref PubMed Scopus (37) Google Scholar Anti-Thy1.1 nephritisratTomooka34Tomooka S. Border W.A. Marshall B.C. Noble N.A. Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.Kidney Int. 1992; 42: 1462-1469Abstract Full Text PDF PubMed Scopus (199) Google Scholar Hypertensive nephropathyratTamaki35Tamaki K. Okuda S. Nakayama M. Yanagida T. Fujishima M. Transforming growth factor-1 in hypertensive renal injury in Dahl salt-sensitive rats.J Am Soc Nephrol. 1996; 7: 2578-2589PubMed Google Scholar Diabetic nephropathymanYamamoto36Yamamoto T. Nakamura T. Noble N.A. Ruoslahti E. Border W.A. Expression of transforming growth factor-β is elevated in human and experimental diabetic nephropathy.Proc Natl Acad Sci USA. 1993; 90: 1814-1818Crossref PubMed Scopus (813) Google Scholar Focal segmental glomerulosclerosismanYamamoto37Yamamoto T. Noble N.A. Cohen A.H. Nast C.C. Hishida A. Gold L.I. Border W.A. Expression of transforming growth factor-β isoforms in human glomerular diseases.Kidney Int. 1996; 49: 461-469Abstract Full Text PDF PubMed Scopus (420) Google Scholar Cyclosporine toxicityratShihab38Shihab F.S. Andoh T.F. Tanner A.M. Noble N.A. Border W.A. Franceschini N. Bennett W.M. Role of transforming growth factor-β1 in experimental chronic cyclosporine nephropathy.Kidney Int. 1996; 49: 1141-1151Abstract Full Text PDF PubMed Scopus (215) Google ScholarratDuymelink39Duymelinck C. Dauwe S.E. Nouwen E.J. De Broe M.E. Verpooten G.A. Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1.Kidney Int. 1997; 51: 1818-1830Abstract Full Text PDF PubMed Scopus (23) Google Scholar Open table in a new tab Plasminogen activator inhibitor type 1 expression is almost undetectable in the normal mouse, rat, and human kidney by immunohistochemistry and in situ hybridization28Xu Y. Hagège J. Mougenot B. Sraer J.D. Rønne E. Rondeau E. Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney.Kidney Int. 1996; 50: 2011-2019Abstract Full Text PDF PubMed Scopus (70) Google Scholar, 29Moll S. Menoud P.A. Fulpius T. Pastore Y. Takahashi S. Fossati L. Vassalli J.D. Sappino A.P. Schifferli J.A. Izui S. Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis.Kidney Int. 1995; 48: 1459-1468Abstract Full Text PDF PubMed Scopus (64) Google Scholar, 42Moll S. Schifferli J.A. Huarte J. Lemoine R. Vassalli J.D. Sappino A.P. LPS induces major changes in the extracellular proteolytic balance in the murine kidney.Kidney Int. 1994; 45: 500-508Abstract Full Text PDF PubMed Scopus (27) Google Scholar. Conversely, it has been shown that t-PA is expressed by endothelial cells in the kidney and by epithelial cells of the inner medulla collecting duct, while u-PA synthesis has been localized in epithelial cells of the proximal tubule, especially in the S3 segment, and in the large ascending limb of the Henle's loop. More recently, the binding of u-PA at the apical membrane of epithelial cells of the collecting duct has been observed. Interestingly, MMP9 binding was also demonstrated at the same place, suggesting a role and perhaps an interaction of luminal proteinases in the collecting duct functions43Piédagnel R. Murphy G. Ronco P.M. Lelongt B. Matrix metalloproteinase 2 (MMP2) and MMP9 are produced by kidney collecting duct principal cells but are differentially regulated by SV40 large-T, arginine vasopressin, and epidermal growth factor.J Biol Chem. 1999; 274: 1614-1620Crossref Scopus (44) Google Scholar. Such a role for luminal proteinases has been recently described for the regulation of the epithelial sodium channel activity44Vallet V. Chraibi A. Gaeggeler H.P. Horisberger J.D. Rossier B.C. An epithelial serine protease activates the amiloride-sensitive sodium channel.Nature. 1997; 389: 607-610Crossref PubMed Scopus (451) Google Scholar. Several studies have shown that PAI-1 synthesis and deposition are promoted in the kidney during experimental and human nephropathies Table 1. PAI-1 deposition may occur along with an inflammatory reaction associated with an activation of coagulation and fibrin deposition in the intravascular or the extravascular spaces42Moll S. Schifferli J.A. Huarte J. Lemoine R. Vassalli J.D. Sappino A.P. LPS induces major changes in the extracellular proteolytic balance in the murine kidney.Kidney Int. 1994; 45: 500-508Abstract Full Text PDF PubMed Scopus (27) Google Scholar,30Yamamoto T. Loskutoff D.J. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator.J Clin Invest. 1996; 97: 2440-2451Crossref PubMed Scopus (181) Google Scholar. In thrombotic microangiopathy25Rondeau E. Mougenot B. Lacave R. Peraldi M.N. Kruithof E.K.O. Sraer J.D. plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies.Clin Nephrol. 1990; 33: 55-60PubMed Google Scholar,28Xu Y. Hagège J. Mougenot B. Sraer J.D. Rønne E. Rondeau E. Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney.Kidney Int. 1996; 50: 2011-2019Abstract Full Text PDF PubMed Scopus (70) Google Scholar, which characterized the pathological pattern of hemolytic uremic syndrome, and in inflammatory glomerulonephritis with extracapillary crescent formation25Rondeau E. Mougenot B. Lacave R. Peraldi M.N. Kruithof E.K.O. Sraer J.D. plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies.Clin Nephrol. 1990; 33: 55-60PubMed Google Scholar, 26Feng L. Tang W.W. Loskutoff D.J. Wilson C.B. Dysfunction of glomerular fibrinolysis in experimental antiglomerular