Inhibition of core fucosylation limits progression of diabetic kidney disease
Inhibition of core fucosylation limits progression of diabetic kidney disease
复制标题
核心岩藻糖基化的抑制可限制糖尿病肾病的进展
DOI：
10.1016/j.bbrc.2019.10.037
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发表时间：
2019-12-10
影响因子：
3.1
通讯作者：
Lin, Hongli
中科院分区：
文献类型：
--
作者：
Fang, Ming;Kang, Le;Lin, Hongli
背景资料：FUT 8介导的核心岩藻糖基化，将岩藻糖残基从GDP-岩藻糖转移到N-连接型糖蛋白的核心-GlcNAc，对信号受体功能至关重要。核心岩藻糖基化参与多种生物学过程，如细胞增殖、凋亡、分化和免疫调节。我们以前的研究表明，抑制核心岩藻糖基化可以预防UUO小鼠模型的肾间质纤维化，但其在糖尿病肾病（DKD）发展中的作用尚不清楚。本研究旨在通过抑制核心岩藻糖基化来阐明DKD的保护作用及其分子机制。方法：在链脲佐菌素（STZ）诱导的糖尿病小鼠模型中检测核心岩藻糖基化。然后构建了一种新的Fut 8突变小鼠模型，其中Fut 8基因外显子7被删除，用于诱导糖尿病。测量代谢和肾脏参数。结果：注射后16周，大鼠空腹血糖、糖化血红蛋白、肾重/体重（KW/ BW）和尿白蛋白/肌酐（ACR）均升高，肾组织病理改变不明显。通过抑制核心岩藻糖基化，KW/BW和尿ACR显著降低。通过抑制核心岩藻糖基化，肾脏病理学、纤维化和足细胞损伤显著减轻。抑制核心岩藻糖基化的保护作用是通过下调Smad 2/3和细胞外信号调节激酶（ERK）的磷酸化来介导的。结论：我们的研究结果表明，以FUT 8为基础的治疗可能是DKD治疗范式中一种有前途的干预策略。(C)2019爱思唯尔公司All rights reserved.
Background: FUT8-mediated core fucosylation, which transfers a fucose residue from GDP-fucose to core-GIcNAc 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. (C) 2019 Elsevier Inc. All rights reserved.