Empagliflozin, a sodium glucose cotransporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-β/Smad signaling
Empagliflozin, a sodium glucose cotransporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-β/Smad signaling
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Empagliflozin 是一种钠葡萄糖协同转运蛋白 2 抑制剂，通过抑制 TGF-β/Smad 信号传导改善腹膜纤维化
DOI：
10.1016/j.intimp.2021.107374
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发表时间：
2021-01-29
影响因子：
5.6
通讯作者：
Zhou, Ying
中科院分区：
文献类型：
--
作者：
Shentu, Yangping;Li, Yuyang;Zhou, Ying
据报道，钠葡萄糖协同转运蛋白-2（SGLT-2）抑制剂在暴露于腹膜透析液的腹膜中发挥降糖作用。然而，SGLT-2抑制剂是否可以通过抑制TGF-β/Smad信号转导来调节腹膜纤维化尚不清楚。我们的目的是（i）检查SGLT-2抑制剂恩格列净在减少炎症反应和预防腹膜透析液诱导的腹膜纤维化方面的作用，（ii）阐明潜在机制。使用高糖腹膜透析液或转化生长因子β 1（TGF-β 1）在体内、小鼠腹膜透析模型（C57 BL/6小鼠）和体外人腹膜间皮细胞中诱导腹膜纤维化，以刺激细胞外基质蓄积。评价了恩格列净和用于抑制SGLT-2活性的腺相关病毒RNAi对腹膜纤维化和细胞外基质的影响。接受慢性腹膜透析溶液输注的小鼠显示腹膜纤维化的典型特征，包括腹膜厚度显著增加、过度基质沉积、腹膜通透性增加以及α-平滑肌肌动蛋白和胶原蛋白I表达上调。恩格列净治疗或下调SGLT-2表达可显著改善这些病理变化。恩格列净治疗组和SGLT-2下调组的炎性细胞因子（TNF-α、IL-1 β、IL-6）和TGF-β/Smad信号相关蛋白（如TGF-β 1和磷酸化Smad（p-Smad 3））减少。此外，恩格列净治疗和SGLT-2表达下调降低了人腹膜间皮细胞中炎性细胞因子（TNF-α、IL-1 β、IL-6）、TGF-β 1、α-平滑肌肌动蛋白、胶原蛋白I和p-Smad 3蓄积的水平。总之，这些结果表明，恩格列净通过抑制TGF-β/Smad信号传导对高糖腹膜透析诱导的腹膜纤维化具有明显的保护作用。
Sodium glucose cotransporter-2 (SGLT-2) inhibitor has been reported to exert a glucose-lowering effect in the peritoneum exposed to peritoneal dialysis solution. However, whether SGLT-2 inhibitors can regulate peritoneal fibrosis by suppressing TGF-beta/Smad signaling is unclear. We aimed to (i) examine the effect of the SGLT-2 inhibitor empagliflozin in reducing inflammatory reaction and preventing peritoneal dialysis solution-induced peritoneal fibrosis and (ii) elucidate the underlying mechanisms. High-glucose peritoneal dialysis solution or transforming growth factor beta 1 (TGF-beta 1) was used to induce peritoneal fibrosis in vivo, in a mouse peritoneal dialysis model (C57BL/6 mice) and in human peritoneal mesothelial cells in vitro, to stimulate extracellular matrix accumulation. The effects of empagliflozin and adeno-associated virus-RNAi, which is used to suppress SGLT-2 activity, on peritoneal fibrosis and extracellular matrix were evaluated. The mice that received chronic peritoneal dialysis solution infusions showed typical features of peritoneal fibrosis, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and upregulated a-smooth muscle actin and collagen I expression. Empagliflozin treatment or downregulation of SGLT-2 expression significantly ameliorated these pathological changes. Inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and TGF beta/Smad signaling-associated proteins, such as TGF-beta 1 and phosphorylated Smad (p-Smad3), decreased in the empagliflozin-treated and SGLT-2 downregulated groups. In addition, empagliflozin treatment and down regulation of SGLT-2 expression reduced the levels of inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), TGF-beta 1, alpha-smooth muscle actin, collagen I, and p-Smad3 accumulation in human peritoneal mesothelial cells. Collectively, these results indicated that empagliflozin exerted a clear protective effect on high-glucose peritoneal dialysis-induced peritoneal fibrosis via suppressing TGF-beta/Smad signaling.