Nephrol Dial Transplant (2006) 1 of 11 doi:10.1093/ndt/gfk076 Original Article Effects of low molecular weight heparin in obstructed kidneys: decrease of collagen, fibronectin and TGF-b, and increase of chondroitin/dermatan sulfate proteoglycans and macrophage infiltration Inah M. D. Pecly 2 , Roˆmulo G. Gonc¸alves 1 , Ednei P. Rangel 1 , Christina M. Takiya 3 , Fernanda S. Taboada 2 , Cesoˆnia A. Martinusso 1 , Mauro S. G. Pava˜o 2 and Maurilo Leite Jr 1 1 Servic¸o de Nefrologia, Departamento de Clı´nica Me´dica, Hospital Universita´rio Clementino Fraga Filho, 2 Laborato´rio de Tecido Conjuntivo, Instituto de Bioquı´mica Me´dica, Programa de Glicobiologia and 3 Departamento de Histologia e Embriologia, Instituto de Cieˆncias Biome´dicas, Universidade Federal do Rio de Janeiro, Brazil Abstract Background. Heparin exerts beneficial effects in different experimental models of nephropathy, as observed by the preservation of the structural morphology of the kidney after heparin therapy. Here we investigate molecular and cellular events involved in the protective effects of heparin in the progression of renal disease after unilateral ureteral obstruction. Methods. Thirty-six rats were divided into six groups: group C (control) was not subjected to any surgical manipulation; group S (sham) was subjected to surgical manipulation but without ureteral ligation; group UUO was subjected to ureteral obstruction and received no treatment; group UUO þ S was subjected to ureteral obstruction and received saline subcuta- neously (s.c.) once daily; group UUO þ H was subjected to ureteral obstruction and received low molecular weight heparin (LMW-Hep; 4 mg/kg) s.c. once daily; and group C þ H was not subjected to any surgical manipulation and received LMW-Hep (4 mg/kg) s.c. once daily. After 14 days, the content of collagen, fibronectin, total glycosaminoglycans (GAGS), chondroitin sulfate/dermatan sulfate proteo- glycans (CS/DSPGs), transforming groth factor-b (TGF-b) and cellular infiltration were determined in the kidneys by immunohistochemical and biochemical techniques. Results. Collagen, fibronectin, total GAGS, CS/ DSPGs, TGF-b and cellular infiltration increased significantly in group UUO. LMW-Hep treatment reduced collagen, fibronectin and TGF-b, but induced an increase in the content of total GAGS, CS/DSPGs and macrophage infiltration in group UUO þ H when compared with group UUO. Conclusions. LMW-Hep diminishes fibrosis in obstructed kidneys by downregulating the synthesis of collagen, fibronectin and TGF-b. The mechanisms underlying the overproduction of CS/DSPGs and the increase in cellular infiltration upon LMW-Hep administration remain to be elucidated. Keywords: animal model; collagen; glycosamino- glycans; low molecular weight heparin; unilateral ureteral obstruction Introduction The pathogenesis of progressive renal diseases leading to renal failure has been the subject of intense investigation. Some features influencing renal inflam- mation and fibrosis have been well recognized, such as matrix deposition, infiltration of blood mononuclear cells, proliferation of interstitial mesenchymal cells, and apoptosis of tubular epithelial cells [1–7]. L-, P- and E-selectin mediate the initial events involving the migration of leukocytes across the endothelium in inflamed tissues [9–13]. Heparin and heparin-like glycosaminoglycans (GAGS) bind to L- and P-selectin and it has been shown that inhibi- tion of these selectins accounts for the potent anti- inflammatory effect of heparin [14]. Heparin has been used successfully as a therapeutic agent in different animal models of nephropathy. Subcutaneous (s.c.) Correspondence and offprint requests to: Maurilo Leite Jr, Rua Ministro Ota´ vio Kelly 296, 302 Nitero´i, R.J. CEP 24220-301, Brazil. Email: mleitejr@hucff.ufrj.br ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org NDT Advance Access published January 26, 2006 at Pennsylvania State University on February 23, 2013 http://ndt.oxfordjournals.org/ Downloaded from