Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China,
Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Kidney Blood Press Res. 2019;44(2):179-187. doi: 10.1159/000498965. Epub 2019 Apr 3.
BACKGROUND/AIMS: Peritoneal fibrosis (PF) is a common complication in patients receiving long-term peritoneal dialysis, which results in damage to peritoneal functions. Epithelial-mesenchymal transition (EMT) is a key step in the early pathogenesis of PF. Increasing evidence has shown that signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in EMT and tissue fibrosis by interacting with distinct EMT-inducing molecules, including transforming growth factor (TGF)-β and advanced glycation end products (AGEs). This study investigated the involvement of STAT3 in the PF process.
We used high glucose-treated human peritoneal mesothelial cell line HMrSV5 as an in vitro model to expose the peritoneal mesothelial cells to high-glucose dialysate. Expression of EMT markers was detected by qRT-PCR. Accumulation of methylglyoxal (MGO) and AGEs in the culture supernatant were measured by enzyme-linked immunosorbent assay. Phosphorylation of STAT3 was assessed by Western blot.
Results showed that high glucose upregulated TGF-β, increased the productions of MGO and AGEs, and induced EMT in HMrSV5 cells. High glucose also activated the STAT3 pathway. STAT3 inhibitor reduced the high glucose-induced EMT, via reducing TGF-β expression and repressing the accumulation of MGO and AGEs.
Our results revealed a critical role for STAT3 signaling in high glucose-induced EMT in HMrSV5 cells, and suggested that inhibition of STAT3 might be a treatment for high glucose-induced fibrogenesis in PF.
背景/目的：腹膜纤维化（PF）是接受长期腹膜透析患者的常见并发症，导致腹膜功能受损。上皮-间充质转化（EMT）是 PF 早期发病机制中的关键步骤。越来越多的证据表明，信号转导子和转录激活子 3（STAT3）信号通路通过与不同的 EMT 诱导分子（包括转化生长因子-β和晚期糖基化终产物（AGEs））相互作用，参与 EMT 和组织纤维化。本研究探讨了 STAT3 在 PF 过程中的作用。
我们使用高糖处理的人腹膜间皮细胞系 HMrSV5 作为体外模型，将腹膜间皮细胞暴露于高糖透析液中。通过 qRT-PCR 检测 EMT 标志物的表达。通过酶联免疫吸附试验测量培养上清液中甲基乙二醛（MGO）和 AGEs 的积累。通过 Western blot 评估 STAT3 的磷酸化。
结果表明，高糖上调 TGF-β，增加 MGO 和 AGEs 的产生，并诱导 HMrSV5 细胞发生 EMT。高糖还激活了 STAT3 通路。STAT3 抑制剂通过降低 TGF-β表达和抑制 MGO 和 AGEs 的积累，减少高糖诱导的 EMT。
我们的结果揭示了 STAT3 信号在 HMrSV5 细胞高糖诱导的 EMT 中的关键作用，并表明抑制 STAT3 可能是治疗 PF 中高糖诱导的纤维发生的一种方法。
