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      "titulo" => "Mecanismos del daño endotelial en la microangiopatía trombótica"
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          "autoresLista" => "G. REMUZZI , A. ESTRADA , F. Casighari , M. Noris , D. Macconi , M. Galbusera"
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      "titulo" => "II. SÍNDROME HEMOLÍTICO URÉMICO. Microangiopatía trombótica"
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    "titulo" => "Mechanisms of intraglomerular coagulation"
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        "autoresLista" => "A. Herting , E. Rondeau"
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    "textoCompleto" => "NEFROLOGÍA. Vol. XXIII. Suplemento 3. 2003 Mechanisms of intraglomerular coagulation A. Hertig and E. Rondeau INSERM U 489. Service de Néphrologie A. Hôpital Tenon. Paris. France. INTRODUCTION Considerable evidence has accumulated involving the activation of the coagulation system, and the insufficiency of the fibrinolysis system, in the pathogenesis of glomerular injury and renal failure. Schematically, when inflammation takes place in the glomerular microenvironment, activated macrophages will produce or induce the local production by resident cells of Tissue Factor (TF). This initiates the cascade of the extrinsic pathway of coagulation, and leads to the activation of thrombin. Hence, formation of a fibrin clot ensues, compromising the glomerular permeability, now dependent of the fibrinolysis countersystem. Fibrinolysis is placed under the control of the enzymatic activity of plasmin, a key-enzyme finely regulated both by activators and inhibitors. These systems are more complex than it appears at first sight, because many of the molecules involved in the coagulation/fibrinolysis processes are multifunctional proteins, and have biological effects outside the vascular compartment, at the intracellu- lar level, through specific receptors expressed at the surface of glomerular resident cells. PART 1. THE COAGULATION SYSTEM IN GLOMERULAR LESIONS Tissue Factor TF synthesis can be induced, in endothelial cells and in macrophages, under appropriate stimuli (i.e. pro-inflammatory cytokines). TF activates the extrinsic pathway by complexing with factor VIIa. In the presence of calcium, Factor X is activated, then Factor V, and eventually prothrombin is converted to active thrombin (fig 1). The key-role of TF was demonstrated in extracapillary glomerulonephritis: in rabbit, concomitant injection of antibodies directed against TF and antibodies directed against glomerular basement membrane (GBM) reduces by half the glomerular lesions (fibrin deposits, formation of crescents), the degree of proteinuria, and of renal failu- Tissue Factor (TF) liberation TF VIIa, Ca2+ + Activation of factor X + Activated Factor V PAR-1 Macrophages + Plasminogen Activator Inhibitor Type 1 (PAI-1) ­ + Plasminogen Activators (t-PA, u-PA) + Plasminogen Plasmin Fibrinolysis ­ Alpha 2 antiplasmin Fig. 1.--Coagulation/Fibrinolysis systems. Fibrinogen + FIBRIN II IIa (Thrombin) 21 A. HERTIG and E. RONDEAU re1. The natural inhibitor of TF, Tissue Factor Pathway Inhibitor (TFPI) could play a protective role in glomerulonephritis, since its synthesis has been demonstrated in the glomerular tuft, in physiologic conditions as well as in pathologic conditions2. TFPI binds Factor Xa to form a complex that secondly binds to TF/VIIa and inhibits TF/VIIa activity. During a model of acute crescentic, fibrinous model of glomerulonephritis in the rabbit, early infusion of recombinant human TFPI protects the glomerulus from fibrin deposition, and attenuates renal impairment, giving convincing arguments that this recombinant protein could be, in a next future, targeted for prevention of fibrinous glomerular lesions3. Thrombin Thrombin is a serine protease predominantly produced on the surface of circulating platelets by the proteolytic activation of its precursor, prothrombin, synthesized by the liver and released into the circulation. On the one hand, thrombin promotes thrombosis by directly activating platelets and by cleaving fibrinogen to monomers of fibrin. On the other hand, thrombin will have cellular biological effects independently of coagulation events, by its interaction with specific receptors, named PAR (for Protease Activated Receptors), belonging to the family of G-protein coupled receptors. PAR-1 is constitutively expressed on the surface of endothelial, mesangial and epithelial cells. Thrombin fixation originally leads to the internal cleavage of the receptor, releasing a small N-terminal peptide and unmasking a new amino-terminal domain that induces the activation of the receptor through intramolecular interactions4. In the kidney, cellular effects of thrombin are multiple, and include the stimulation of the proliferation of fibroblasts, and of glomerular epithelial cells present in the crescents5. During human acute glomerulonephritis, it has been observed that PAR-1 protein expression on the surface of glomerular cells was down-regulated whereas its specific messenger RNA was, on the contrary, up-regulated6. This strongly suggests the internalization of the receptor activated by thrombin, as observed in vitro. Cunningham has distinguished, during experimental glomerulonephritis, the extracellular (procoagulant) effects of thrombin through its capacity to form fibrin from its cellular (pro-inflammatory) effects through the activation of PAR-17. Hirudin, a potent serine protease inhibitor, drastically reduces the glomerular lesions induced in mice by the injection of anti-GBM antibodies. This is true for the infiltration by macrophages, fibrin deposition, and crescent formation. 22 And, on the other hand, administration of peptide TRAP (capable of direct transactivation of PAR-1 without the enzymatic properties of thrombin) accentuates the glomerular lesions, and mice knock-out for PAR-1 are as protected as hirudin-treated mice, suggesting that the main mechanism of action of thrombin is mediated through its cellular, pro-inflammatory effects on glomerular cells, rather than through its pro-coagulant effects. Fibrin Fibrin clot is the end product of the coagulation cascade. It not only compromises the glomerular capillary flow, leading to focal ischemia and necrosis, but also exerts chemotactic support for macrophages and leukocytes, thus allowing the enhancement of the inflammatory reaction. It has long been observed that defibrination by ancrod reduces the severity of glomerulonephritis8. More recently, the model of acute glomerulonephritis consecutive to the injection of anti-GBM antibodies has been tested in mice with a deletion within the gene encoding the A chain of fibrinogen9. These mice have no circulating fibrinogen, and thus cannot form fibrin clots in the injured glomeruli. Yet, diffuse glomerulonephritis is still observed, with «evident» crescents, and the level of proteinuria is unaffected. PART 2. THE FIBRINOLYSIS SYSTEM Plasminogen Activators Fibrinolysis system can be summarized by the action of plasmin, a key-enzyme responsible for the destruction of fibrin (fig 1). Plasmin is generated from plasminogen by the catalytic action of tissuetype plasminogen activator (t-PA), and of receptor bound (u-PAR) urokinase-type plasminogen activator (u-PA). These two activators are not redundant: t-PA, with a high affinity towards fibrin, serves as a mediator of intravascular fibrinolysis, whereas u-PA converts plasminogen into plasmin at the cellular surface expressing u-PAR, mediating the proteolytic action of plasmin, and extracellular matrix remodeling (plasmin can directly degrade numerous substrates of ECM). The beneficial effect of plasminogen activators was confirmed when anti-GBM glomerulonephritis was found to be more severe in mice knock-out for t-PA and for plasminogen: they develop more crescents, more fibrin deposition, and more severe renal failure when compared to wildtype mice10. Mice knock-out for u-PA or for its re- MECHANISMS OF INTRAGLOMERULAR COAGULATION ceptor show on the contrary no difference when compared to wild-type animals. Recombinant tissuePA has been proved to be a protective therapeutic agent in animal models of acute crescentic glomerulonephritis11. Plasminogen Activator Inhibitors Despite the enhanced synthesis of plasminogen activators in injured glomeruli, it remains that the net intraglomerular fibrinolytic activity is diminished12. This suggests that fibrinolysis is blunted by a dominant increase of anti-fibrinolytic agents, such as plasminogen activator inhibitors and / or alpha-2 antiplasmin. Four plasminogen activator inhibitors have been discovered. The main one, plasminogen activator inhibitor type 1 (PAI-1), is a glycoprotein belonging to the serpin family (SERine Protease INhibitor). Under physiological conditions, PAI-1 is not physiologically synthesized by the kidney. However, in experimental models of crescentic glomerulonephritis induced by anti-GBM antibodies in rats, an early and long-lasting up-regulation of PAI-1 gene transcription and PAI-1 biological activity is observed13. In human, under pathological conditions, such as acute crescentic glomerulonephritis with fibrin deposits, or vascular nephropathy, its paradoxical presence has been detected by immunofluorescence and in situ hybridization14. The level of PAI-1 activity could influence the course of various nephropathies with glomerular fibrin deposistion, as suggested by the recent findings that the 4G/4G genotype for PAI-1 gene, associated with higher plasmatic concentration and activity of PAI-1, was associated with a higher nephritis activity and more extensive necrotizing lesions in patients with sytemic lupus erythematosus15. Recently, Chandler et al have also shown that the plasma concentration of PAI-1 was predictive for the development of a hemolytic uremic syndrome at the early phase of enteric infection with Escherichia coli O157:H716. Alpha 2-antiplasmin Alpha 2-antiplasmin is the physiological inhibitor of plasmin. Its production is essentially hepatic, and renal. Alpha 2-antiplasmin is a serpin that directly targets plasmin to form a stable, inactive complex, and also has a fixation domain recognizing plasminogen, competitive for the fixation of plasminogen to fibrin. As such, alpha 2-antiplasmin is a potent anti-fibrinolytic molecule. In an acute fibrin-dependant model of glomerular injury in mice, Dewerchin and coll. have found that invalidation of PAI-1 is not protective, by contrast with invalidation of alpha-2 antiplasmin17. CONCLUSION In summary, during glomerular injury, local production of procoagulant and anti-fibrinolytic agents tips the balance existing between both systems towards fibrin deposition. While most of the data reviewed here are issued from experimental work, we may hope that a new therapeutic approach will emerge in the treatment of fibrinous glomerulonephritis, and improve their bad outcome. REFERENCES 1. Erlich JH, Holdsworth SR, Tipping PG: Tissue factor initiates glomerular fibrin deposition and promotes major histocompatibility complex class II expression in crescentic glomerulonephritis. Am J Pathol 150: 873-80, 1997. 2. Cunningham MA, Ono T, Hewitson TD, Tipping PG, Becker GJ, Holdsworth SR: Tissue Factor Pathway Inhibitor expression in human crescentic glomerulonephritis. Kidney Int 55: 1311-1318, 1999. 3. Erlich JH, Apostolopoulos J, Wun TC, Kretzmer KK, Holdsworth SR, Tipping PG: Renal expression of tissue factor pathway inhibitor and evidence for a role in crescentic glomerulonephritis in rabbits. J Clin Invest 98: 325-35, 1996. 4. Vu TK, Hung DT, Wheaton VI, Coughlin SR: Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057-68, 1991. 5. He CJ, Rondeau E, Medcalf RL, Lacave R, Schleuning WD, Sraer JD: Thrombin increases proliferation and decreases fibrinolytic activity of kidney glomerular epithelial cells. J Cell Physiol 146: 131-40, 1991. 6. Xu Y, Zacharias U, Peraldi MN, He CJ, Lu C, Sraer JD, Brass LF, Rondeau E. Constitutive expression and modulation of the functional thrombin receptor in the human kidney. Am J Pathol 146: 101-10, 1995. 7. Cunningham MA, Rondeau E, Chen X, Coughlin SR, Holdsworth SR, Tipping PG: Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J Exp Med 191: 455-62, 2000. 8. Thomson NM, Simpson IJ, Peters DK: A quantitative evaluation of anticoagulants in experimental nephrotoxic nephritis. Clin Exp Immunol 19: 301-8, 1975. 9. Drew AF, Tucker HL, Liu H, Witte DP, Degen JL, Tipping PG: Crescentic glomerulonephritis is diminished in fibrinogen-deficient mice. Am J Physiol 281: F1157-F1163, 2001. 10. Kitching AR, Holdsworth SR, Ploplis VA, Plow EF, Collen D, Carmeliet P, Tipping PG: Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med 185: 963-8, 1997. 11. Zoja C, Corna D, Macconi D, Zilio P, Bertani T, Remuzzi G. Tissue plasminogen activator therapy of rabbit nephrotoxic nephritis. Lab Invest 62: 34-40, 1990. 12. Malliaros J, Holdsworth SR, Wojta J, Erlich J, Tipping PG: Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits. Kidney Int 44: 557-64, 1993. 23 A. HERTIG and E. RONDEAU 13. Feng L, Tang WW, Loskutoff DJ, Wilson CB: Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. J Am Soc Nephrol 3: 1753-64, 1993. 14. Xu Y, Hagege J, Mougenot B, Sraer JD, Ronne E, Rondeau E: Different expression of the plasminogen activation system in renal thrombotic microangiopathy and the normal human kidney. Kidney Int 50: 2011-9, 1996. 15. Wang AY, Poon P, Lai FM, Yu L, Choi PC, Lui SF, Li PK: Plasminogen activator inhibitor-1 gene polymorphism 4G/4G ge- notype and lupus nephritis in Chinese patients. Kidney Int 59: 1520-8, 2001. 16. Chandler WL, Jelacic S, Boster DR, Ciol MA, Williams GD, Watkins SL, Igarashi T, Tarr PI. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med 346: 23-32, 2002. 17. Dewerchin M, Collen D, Lijnen HR: Enhanced fibrinolytic potential in mice with combined homozygous deficiency of alpha 2-antiplasmin and PAI-1. Thromb Haemost 86: 640-6, 2001. 24 "
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