Diabetic nephropathy (DN) is a complication of diabetes, which leads to most end-stage kidney diseases and threatens health of patients. Mucin 1 (MUC1) is a heterodimeric oncoprotein, which is abnormally expressed in tumors and hematologic diseases. The aim of this study is to clarify the mechanism and role of MUC1 in DN. The mesangial cells (MCs) suffered from high glucose (HG) treatment to mimic DN in vitro. The cell proliferation was detected by Cell Counting Kit-8 assay and 5-ethynyl-2-deoxyuridine (EdU) staining assay. The expression of MUC1 and fibrosis markers: fibronectin, collagen I, and collagen IV were assessed by western blot. In this study, we demonstrated that HG treatment induced MUC1 expression in MCs. With knockdown of MUC1 or overexpressed MUC1 in MCs, the results indicated that knockdown of MUC1 inhibited MCs proliferation and reduced kidney fibrosis markers expression, including fibronectin, collagen I, and collagen IV, whereas overexpression of MUC1 led to opposite results. Mechanically, MUC1 activated signal transducers and activators of transcription (STAT) and β-catenin signal pathway. After added AG490 (STAT inhibitor) or FH535 (β-catenin inhibitor), blocking STAT3 and β-catenin signal pathway attenuated MUC1-induced cell proliferation and fibronectin production in MCs. Finally, knockdown of MUC1 attenuated DN-induced kidney fibrosis in db/db mice. Therapeutic target for DN. In conclusion, MUC1 promotes MCs proliferation and kidney fibrosis in DN through activating STAT and β-catenin signal pathway, which can help to provide a novel therapeutic target for DN.

中文翻译：

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MUC1通过激活STAT和β-Catenin信号通路促进糖尿病肾病系膜细胞增殖和肾纤维化

糖尿病肾病（DN）是糖尿病的一种并发症，可导致大多数终末期肾脏疾病，威胁患者的健康。粘蛋白 1 (MUC1) 是一种异源二聚体癌蛋白，在肿瘤和血液系统疾病中异常表达。本研究旨在阐明MUC1在DN中的作用机制和作用。系膜细胞 (MC) 遭受高糖 (HG) 处理以在体外模拟 DN. 通过Cell Counting Kit-8测定和5-乙炔基-2-脱氧尿苷（EdU）染色测定检测细胞增殖。MUC1 的表达和纤维化标志物：纤连蛋白、胶原蛋白 I 和胶原蛋白 IV 通过蛋白质印迹评估。在这项研究中，我们证明了 HG 处理诱导了 MCs 中的 MUC1 表达。随着 MUC1 的敲低或 MUC1 在 MC 中的过表达，结果表明 MUC1 的敲低抑制了 MC 的增殖并减少了肾纤维化标志物的表达，包括纤连蛋白、胶原蛋白 I 和胶原蛋白 IV，而 MUC1 的过度表达导致相反的结果。在机械上，MUC1 激活信号转导和转录激活因子 (STAT) 和 β-catenin 信号通路。添加AG490（STAT抑制剂）或FH535（β-catenin抑制剂）后，阻断 STAT3 和 β-连环蛋白信号通路减弱了 MUC1 诱导的 MC 细胞增殖和纤连蛋白产生。最后，在 db/db 小鼠中，MUC1 的敲低减弱了 DN 诱导的肾纤维化。DN 的治疗靶点。综上所述，MUC1通过激活STAT和β-catenin信号通路促进DN中MCs增殖和肾纤维化，有助于为DN提供新的治疗靶点。