BACKGROUND: Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM), is a common histopathological feature of progressive renal disease of diverse etiology. Interaction between transforming growth factor-beta (TGF-beta) and TGF-beta type II receptor (TGF-betaIIR) may play an important role in the ongoing fibrotic process. TGF-betaIIR and TGF-beta have been reported to be up-regulated in human glomerulopathies. In order to block the TGF-beta system, many studies have inhibited TGF-beta itself, but not its receptors. Our study explored the effects of fully human monoclonal antibody against TGF-betaIIR (hTGF-betaIIRAb) on experimental proliferative glomerulonephritis. METHODS: hTGF-betaIIRAb was generated from Xenomice. The expression of TGF-betaIIR was studied by immunohistochemistry in normal and anti-Thy-1 nephritis rats. hTGF-betaIIRAb or control Ab was injected intraperitoneally at day 0 and day 4 of anti-Thy-1 nephritis, and rats were sacrificed at day 7. Effects of hTGF-betaIIRAb were assessed by histological and immunopathological measurements. RESULTS: The specificity of hTGF-betaIIRAb was confirmed by ELISA and Western blot analysis. By immunostaining, TGF-betaIIR expression was up-regulated in the proliferative lesions of anti-Thy-1 nephritis at day 7. In the hTGF-betaIIRAb-treated group, the extent of mesangial expansion was less than that in the control group. By immunohistology, alpha-smooth muscle actin, fibronectin-EDA, and type I collagen were significantly reduced in the hTGF-betaIIRAb-treated group. CONCLUSIONS: Anti-TGF-betaIIR antibody ameliorated ECM accumulation in anti-Thy-1 nephritis. Our data suggest that TGF-betaIIR may be one of the therapeutic targets, and that fully human monoclonal antibody against TGF-betaIIR may have a new therapeutic potential for renal fibrosis.
BACKGROUND:Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM), is a common histopathological feature of progressive renal disease of diverse etiology. Interaction between transforming growth factor-beta (TGF-beta) and TGF-beta type II receptor (TGF-betaIIR) may play an important role in the ongoing fibrotic process. TGF-betaIIR and TGF-beta have been reported to be up-regulated in humanglomerulopathies. In order to block the TGF-beta system, many studies have inhibited TGF-beta itself, but not its receptors. Our study explored the effects of fully human monoclonal antibody against TGF-betaIIR (hTGF-betaIIRAb) on experimental proliferative glomerulonephritis. METHODS: hTGF-betaIIRAb was generated from Xenomice. The expression of TGF-betaIIR was studied by immunohistochemistry in normal and anti-Thy-1nephritisrats. hTGF-betaIIRAb or control Ab was injected intraperitoneally at day 0 and day 4 of anti-Thy-1nephritis, and rats were sacrificed at day 7. Effects of hTGF-betaIIRAb were assessed by histological and immunopathological measurements. RESULTS: The specificity of hTGF-betaIIRAb was confirmed by ELISA and Western blot analysis. By immunostaining, TGF-betaIIR expression was up-regulated in the proliferative lesions of anti-Thy-1nephritis at day 7. In the hTGF-betaIIRAb-treated group, the extent of mesangial expansion was less than that in the control group. By immunohistology, alpha-smooth muscle actin, fibronectin-EDA, and type I collagen were significantly reduced in the hTGF-betaIIRAb-treated group. CONCLUSIONS: Anti-TGF-betaIIR antibody ameliorated ECM accumulation in anti-Thy-1nephritis. Our data suggest that TGF-betaIIR may be one of the therapeutic targets, and that fully human monoclonal antibody against TGF-betaIIR may have a new therapeutic potential for renal fibrosis.
Authors: Sydney R Murphy; Annette J Dahly-Vernon; Kathryn M J Dunn; Chun Cheng Andy Chen; Steven R Ledbetter; Jan M Williams; Richard J Roman Journal: Am J Physiol Regul Integr Comp Physiol Date: 2012-04-25 Impact factor: 3.619
Authors: Kyungmin Hahm; Matvey E Lukashev; Yi Luo; William J Yang; Brian M Dolinski; Paul H Weinreb; Kenneth J Simon; Li Chun Wang; Diane R Leone; Roy R Lobb; Donald J McCrann; Normand E Allaire; Gerald S Horan; Agnes Fogo; Raghu Kalluri; Charles F Shield; Dean Sheppard; Humphrey A Gardner; Shelia M Violette Journal: Am J Pathol Date: 2007-01 Impact factor: 4.307