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-β1) 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-β signaling for antifibrotic therapy. Here, we investigated the mode of action of glucosamine hydrochloride (GS-HCl) on TGF-β1-induced renal fibrosis. In the obstructed kidneys and TGF-β1-treated renal cells, GS-HCl significantly decreased renal expression of α-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-β signaling by inhibiting N-linked glycosylation of the type II TGF-β receptor (TβRII), leading to an inefficient trafficking of TβRII to the membrane surface. Defective N-glycosylation of TβRII further suppressed the TGF-β1-binding to TβRII, thereby decreasing TGF-β signaling. Notably, GS-HCl treatment significantly reduced TGF-β1-induced up-regulation of Smad2/3 phosphorylation and transcriptional activity in vivo and in vitro. Taken together, GS-HCl-mediated regulation of TGF-β 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-β1-induced renal fibrosis in kidney diseases.


CONCLUSIONS
Glucosamine-mediated attenuation of TGF-β signaling ameliorates renal fibrosis in vivo TGF-β1-induced fibrogenic action is reduced by glucosamine in vitro N-glycosylation of the type II TGF-β receptor is suppressed by glucosamine Glucosamine-induced defective N-glycosylation of TβRII decreases TGF-β signaling.
CHA Cancer Institute, CHA University, 605 Yeoksam-dong, Gangnam-gu, Seoul, 135-081, South Korea.
Jinah
J
Park
So-Young
SY
Lee
Akira
A
Ooshima
Kyung-Min
KM
Yang
Jin Muk
JM
Kang
Young-Woong
YW
Kim
Seong-Jin
SJ
Kim
D000818:Animals; D002460:Cell Line; D005355:Fibrosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D005944:Glucosamine / Q000627:therapeutic use*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D005944:Glucosamine