Glucosamine hydrochloride exerts a protective effect against unilateral ureteral obstruction-induced renal fibrosis by attenuating TGF-β signaling

Renal fibrosis is a common consequence of unilateral ureteral obstruction, which provides a useful model to investigate the pathogenesis of obstructive nephropathy and progressive renal fibrosis. Transforming growth factor (TGF-beta 1) has been recognized as a key mediator in renal fibrosis by stimulating matrix-producing fibrogenic cells and promoting extracellular matrix deposition. Therefore, considerable efforts have been made to regulate TGF-beta signaling for antifibrotic therapy. Here, we investigated the mode of action of glucosamine hydrochloride (GS-HCl) on TGF-beta 1-induced renal fibrosis. In the obstructed kidneys and TGF-beta 1-treated renal cells, GS-HCl significantly decreased renal expression of alpha-smooth muscle actin, collagen I, and fibronectin. By investigating the inhibitory mechanism of GS-HCl on renal fibrosis, we found that GS-HCl suppressed TGF-beta signaling by inhibiting N-linked glycosylation of the type II TGF-beta receptor (T beta RII), leading to an inefficient trafficking of T beta RII to the membrane surface. Defective N-glycosylation of T beta RII further suppressed the TGF-beta 1-binding to T beta RII, thereby decreasing TGF-beta signaling. Notably, GS-HCl treatment significantly reduced TGF-beta 1-induced up-regulation of Smad2/3 phosphorylation and transcriptional activity in vivo and in vitro. Taken together, GS-HCl-mediated regulation of TGF-beta signaling exerted an antifibrotic effect, thereby ameliorating renal fibrosis. Our study suggests that GS-HCl would be a promising agent for therapeutic intervention for preventing TGF-beta 1-induced renal fibrosis in kidney diseases. Glucosamine-mediated attenuation of TGF-beta signaling ameliorates renal fibrosis in vivo TGF-beta 1-induced fibrogenic action is reduced by glucosamine in vitro N-glycosylation of the type II TGF-beta receptor is suppressed by glucosamine Glucosamine-induced defective N-glycosylation of T beta RII decreases TGF-beta signaling.