© 2008 Schattauer GmbH, Stuttgart 90 Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency Nelson E. Bruno 1 , Yutaka Yano 1 , Yoshiyuki Takei 3 , Liqiang Qin 4 ,Toshinari Suzuki 1 , John Morser 4,7 , Corina N. D’Alessandro-Gabazza 2 , Akira Mizoguchi 6 , Koji Suzuki 5 , OsamuTaguchi 2 , Esteban C. Gabazza 4 , Yasuhiro Sumida 1 1 Department of Diabetes and Endocrinology, 2 Department of Pulmonary and CriticalCare Medicine, 3 Department of Gastroenterology and Hepatology, 4 Department of Immunology, 5 Department of Molecular Pathobiology, 6 Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine,Tsu-city, Mie, Japan; 7 Department of Cardiovascular Research, Berlex Biosciences, Richmond, California, USA Summary The activity of plasmin plays a critical role in the development of chronic glomerulonephritis.Thrombin-activatable fibrinolysis in- hibitor (TAFI) is a potent inhibitor of plasmin generation.We hy- pothesized thatTAFI is involved in the pathogenesis of glomeru- lonephritis because it inhibits plasmin generation.To demon- strate this hypothesis, we compared the development of im- mune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulo- nephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addi- Keywords Knockout mouse, glomerulonephritis, coagulation, fibrin, cyto- kines, plasmin, inflammation tion, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were signifi- cantly decreased inTAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI- knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may consti- tute a novel molecular target for the therapy of this disease. Thromb Haemost 2008; 100: 90–100 Wound Healing and Inflammation / Infection Correspondence to: Esteban C. Gabazza, MD, PhD Department of Immunology, Mie University Graduate School of Medicine Edobashi 2–174, Tsu-city, 514–8507 Mie, Japan Tel.: +81 59 231 3180, Fax: +81 59 231 3180 E-mail: gabazza@clin.medic.mie-u.ac.jp Financial support The present investigation was supported by Grants-in-Aid (nos. 18590846, 17590788) from the Ministry of Education, Culture, Sports, Science andTechnology of Japan, and by Grants-in-Aids from the Mie Medical Research (2006), Okasan-Kato Foundation (2007) and Suzuken Memorial (2005) Foundations, and the Mie University COE Project Fund. Received February 18, 2008 Accepted after major revision May 20, 2008 Prepublished online June 11, 2008 doi:10.1160/TH08-02-0092 Introduction The deposition of immune complex in the kidneys is a frequent cause of chronic glomerulonephritis and subsequent renal fail- ure (1). The presence of immune complexes in the glomerular structures causes renal cell injury by activating the complement system, by stimulating the infiltration of inflammatory cells and by inducing the secretion of vasoactive substances, adhesion molecules, cytokines and pro-coagulant factors from resident cells (1–2). This initial inflammatory response may ultimately evolve to an end-stage renal fibrosis, which is characterized by increased accumulation of myofibroblasts, excessive deposition of extracellular matrix proteins (e.g. collagen), progressive des- truction of glomeruli and renal failure (3–4). Glomerulonephri- tis caused by immune complex in humans are serum sickness disease and autoimmune diseases such as systemic lupus erythe- matosus, subacute bacterial endocarditis and hepatitis C-related cryoglobulinemia (1).The mechanistic pathways involved in the transition from tissue injury to fibrosis in the kidneys are not understood but decreased local activation of extracellular ma- trix-degrading enzymes may play a critical role (5–7). An impor- tant physiological activator of matrix degradation in the kidneys is the plasminogen-plasmin system (8–9). A balance between the processes of degradation and deposition of extracellular matrix is a fundamental requisite for maintaining the structural and functional integrity of the glomerulus (5). Thus, decreased activ- For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2018-03-02 | ID: 1001066444 | IP: 54.70.40.11