MUC1 Promotes Mesangial Cell Proliferation and Kidney Fibrosis in Diabetic Nephropathy Through Activating STAT and beta-Catenin Signal Pathway

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 beta-catenin signal pathway. After added AG490 (STAT inhibitor) or FH535 (beta-catenin inhibitor), blocking STAT3 and beta-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 beta-catenin signal pathway, which can help to provide a novel therapeutic target for DN.