Abstract
Pericytes have been identified as a major source of myofibroblasts in renal interstitial fibrosis (RIF). The overactivation of several signaling pathways, mainly the TGF-β and PDGF pathways, initiates the pericyte-myofibroblast transition during RIF. Key receptors in these two pathways have been shown to be modified by fucosyltransferase 8 (FUT8), the enzyme that catalyzes core fucosylation. This study postulated that core fucosylation might play an important role in regulating the pericyte transition in RIF. The data showed that core fucosylation increased with the extent of RIF in patients with IgA nephropathy (IgAN). Similarly, core fucosylation of pericytes increased in both a unilateral ureteral occlusion (UUO) mouse model and an in vitro model of pericyte transition. Inhibition of core fucosylation by adenoviral-mediated FUT8 shRNA in vivo and FUT8 siRNA in vitro significantly reduced pericyte transition and RIF. In addition, the activation of both the TGF-β/Smad and PDGF/ERK pathways was blocked by core fucosylation inhibition. In conclusion, core fucosylation may regulate the pericyte transition in RIF by modifying both the TGF-β/Smad and PDGF/ERK pathways. Glycosylation might be a novel “hub” target to prevent RIF.
Highlights
Based on the results of our previous study and other reports, core fucosylation modifies TGF-βR and PDGFRβ; inhibition of the core fucosylation of TGF-βR alleviates renal interstitial fibrosis (RIF) in rat models of unilateral ureteral obstruction (UUO) and renal tubular cell injury in vitro[20,21]
Core fucosylation of proteins is catalyzed by α1,6-fucosyltransferase (FUT8) in the Golgi apparatus, which adds fucose to the innermost GlcNAc residue of N-linked oligosaccharides on glycoproteins, and this modification is preferentially recognized by Lens culinaris lectin (LCA)[22,23,24]
These findings indicated that core fucosylation of pericytes increased when pericytes were activated in the RIF process of patients with IgA nephropathy (IgAN)
Summary
Based on the results of our previous study and other reports, core fucosylation modifies TGF-βR and PDGFRβ; inhibition of the core fucosylation of TGF-βR alleviates RIF in rat models of unilateral ureteral obstruction (UUO) and renal tubular cell injury in vitro[20,21]. Core fucosylation of proteins is catalyzed by α1,6-fucosyltransferase (FUT8) in the Golgi apparatus, which adds fucose to the innermost GlcNAc residue of N-linked oligosaccharides on glycoproteins, and this modification is preferentially recognized by Lens culinaris lectin (LCA)[22,23,24]. This study postulated that core fucosylation might be a potential target to simultaneously prevent these two receptors from triggering the activation of downstream intermediates. We investigated the effect of core fucosylation on the activities of both the TGF-β/Smad and PDGF/ERK pathways during the pericyte transition in RIF. The down-regulation of core fucosylation prevented the pericyte transition and RIF by inhibiting the activities of both the TGF-β/Smad and PDGF/ERK pathways. This study is the first to suggest that the core fucosylation of pericytes represents a promising “hub” target for RIF
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