Tao Yiying, Han Jianfang, Liu Wenhua, An Ling, Hu Wenbo, Wang Ningning, Yu Yean
Department of Nephrology, Qinghai Provincial People's Hospital, Xining City, China.
Department of Nephrology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan City, China.
DNA Cell Biol. 2021 Oct;40(10):1308-1316. doi: 10.1089/dna.2021.0098. Epub 2021 Sep 14.
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 . 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.
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病并威胁患者健康。黏蛋白1（MUC1）是一种异二聚体癌蛋白，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。用高糖（HG）处理系膜细胞（MCs）以模拟DN。通过细胞计数试剂盒-8法和5-乙炔基-2'-脱氧尿苷（EdU）染色法检测细胞增殖。通过蛋白质印迹法评估MUC1和纤维化标志物（纤连蛋白、I型胶原和IV型胶原）的表达。在本研究中，我们证明HG处理可诱导MCs中MUC1的表达。在MCs中敲低或过表达MUC1后，结果表明敲低MUC1可抑制MCs增殖并降低肾纤维化标志物的表达，包括纤连蛋白、I型胶原和IV型胶原，而过表达MUC1则导致相反的结果。机制上，MUC1激活信号转导和转录激活因子（STAT）和β-连环蛋白信号通路。加入AG490（STAT抑制剂）或FH535（β-连环蛋白抑制剂）后，阻断STAT3和β-连环蛋白信号通路可减弱MUC1诱导的MCs增殖和纤连蛋白产生。最后，敲低MUC1可减轻db/db小鼠DN诱导的肾纤维化。DN的治疗靶点。总之，MUC1通过激活STAT和β-连环蛋白信号通路促进DN中MCs增殖和肾纤维化，这有助于为DN提供一种新的治疗靶点。
