Inhibition of core fucosylation limits progression of diabetic kidney disease

Abstract

Background: FUT8-mediated core fucosylation, which transfers a fucose residue from GDP-fucose to core-GlcNAc of the N-linked type glycoproteins, is crucial for signaling receptors function. Core fucosylation is involved in various biological processes such as cell proliferation, apoptosis, differentiation and immune regulation. Our previous studies demonstrated that inhibiting core fucosylation prevented renal interstitial fibrosis of UUO murine models, but its role in the development of diabetic kidney disease (DKD) remains unclear. This study aimed to clarify the protective effects and molecular mechanisms during the progress of DKD by inhibiting core fucosylation in vivo.

Methods: Core fucosylation was examined in streptozotocin (STZ)-induced diabetic mouse model. Then a new Fut8 mutation mouse model in which exon 7 of Fut8 gene is deleted was constructed for diabetes induction. Metabolic and renal parameters were measured. Renal structure, fibrosis, and podocyte injury were assessed, and underlying mechanisms were investigated.

Results: The levels of fasting blood glucose, glycated hemoglobin, kidney-weight-to- body-weight (KW/BW) and urine albumin-to-creatinine (ACR) were increased at 16 weeks post injection. KW/BW and urine ACR were decreased significantly by inhibiting core fucosylation. The renal pathology, fibrosis, and podocyte injury were mitigated significantly by inhibiting core fucosylation. The protective effects of inhibiting core fucosylation were mediated by downregulated of the phosphorylation of Smad2/3 and extracellular signal-regulated kinase (ERK).

Conclusions: Our results indicate that FUT8-based treatment might be a promising intervention strategy in therapeutic paradigm of DKD.

Keywords: Core fucosylation; Diabetic kidney disease; FUT8; Podocyte.