ANTI-LATENT TGF-BETA BINDING PROTEIN-1 ANTIBODY OR SYNTHETIC OLIGOPEPTIDES INHIBIT EXTRACELLULAR-MATRIX EXPRESSION INDUCED BY STRETCH IN CULTURED RAT MESANGIAL CELLS

Transforming growth factor-beta (TGF-beta) is usually secreted as a la rge latent complete associated with latent TGF-beta binding protein-1 (LTBP-1), which is known to bind to extracellular matrix (ECM) compone nts. Although the LTBP-ECM interaction has been suggested to play a ro le in the activation and biological action of TGF-beta, the precise me chanism is still unclear. In glomerular hypertension mes angial cells are believed to perceive the increased cyclic strain and we have recen tly reported that cyclic mechanical stretch in vitro enhances the expr ession of ECM components via an autocrine/paracrine secretion of TGF-b eta in cultured rat mesangial cells. Therefore, in this study we exami ned the role of LTBP-1 in the stretch-induced, TGF-beta-mediated ECM e xpression. Mesangial cells expressed mRNA for short and long forms of LTBP-1 (LTBP-1S and LTBP-1L, respectively). Mesangial cells were subje cted to cyclic stretch to provide a maximal elongation of 20% at a rat e of 60 cycles/min for 24 to 36 hours in the presence of polyclonal an tibody raised against human LTBP-1 or synthetic oligopeptides correspo nding to the N-terminal portions of human LTBP-1, which may work as co mpetitive inhibitors against the LTBP-ECM association. Both anti-LTBP- 1 antibody (Ab39) and synthetic oligopeptides inhibited the stretch-in duced mRNA expression of type I collagen and fibronectin in a dose-dep endent manner, but the inhibition by Ab39 or the oligopeptides was rec overed by adding recombinant TGF-beta. Ab39 or the oligopeptides did n ot change the effect of exogenously added TGF-beta, such as growth-inh ibition in mink lung epithelial cells. These results suggest that mesa ngial cells secrete TGF-beta as a large latent complex, and the LTBP-E CM interaction may be a pivotal step in TGF-beta action and ECM accumu lation, providing a new therapeutic strategy against progression of gl omerulosclerosis and other fibrotic diseases.