Klotho prevents epithelial–mesenchymal transition through Egr-1 downregulation in diabetic kidney disease

作者：Li Yang, Meng Xue, Fang Hu, Yijie Jia, Zongji Zheng, Yanlin Yang, Yanlin Yang, Xiaolian Liu, Yuelian Yang, Yuelian Yang, Yanjing Wang · 发表于：BMJ Open Diabetes Research & Care · 年份：2021 · DOI：10.1136/bmjdrc-2020-002038 · 被引用次数：27 · 研究领域：Parathyroid Disorders and Treatments、Chronic Kidney Disease and Diabetes、Dialysis and Renal Disease Management

INTRODUCTION: As a key event leading to tubulointerstitial fibrosis in diabetic kidney disease (DKD), epithelial-mesenchymal transition (EMT) has drawn increasing attention from researchers. The antiaging protein Klotho attenuates renal fibrosis in part by inhibiting ERK1/2 signaling in DKD. Early growth response factor 1 (Egr-1), which is activated mainly by ERK1/2, has been shown to play an important role in EMT. However, whether Klotho prevents EMT by inhibiting ERK1/2-dependent Egr-1 expression in DKD is unclear.The aim of this study was to investigate whether Klotho prevents EMT through Egr-1 downregulation by inhibiting the ERK1/2 signaling pathway in DKD. RESEARCH DESIGN AND METHODS: Male C57BL/6J mice fed an high-fat diet for 4 weeks received 120 mg/kg streptozotocin (STZ), which was injected intraperitoneally. Klotho and Egr-1 expression was detected in the renal cortices of these mice on their sacrifice at 6 and 12 weeks after STZ treatment. In In vitro studies, we incubated HK2 cells under high-glucose (HG) or transforming growth factor-β1 (TGF-β1) conditions to mimic DKD. We then transfected the cells with an Klotho-containing plasmid, Klotho small interfering RNA. RESULTS: Klotho expression was significantly decreased in the renal cortices of mice with diabetes mellitus (DM) compared with the renal cortices of control mice at 6 weeks after treatment and even more significantly decreased at 12 weeks. In contrast, Egr-1 expression was significantly increased in mic...