FOSL2 activates TGF-β1-mediated GLUT1/mTOR signaling to promote diabetic kidney disease.

IF 3.2 3区医学

Journal of Diabetes Investigation Pub Date : 2024-11-21 DOI:10.1111/jdi.14360

Xuelin He, Min Xia, Guanghui Ying, Qien He, Zhaogui Chen, Li Liu, Qiao Zhang, Jianxin Cai

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Abstract

Aims/introduction: Diabetic kidney disease (DKD) is a major cause of kidney failure. FOS-like antigen 2 (FOSL2) has been revealed to be increased in kidney biopsies of patients with lupus nephritis, while its association with DKD remains unsolved. This study aimed to characterize the role of FOSL2 in DKD and its mechanism.

Method: The kidney tissues of DKD mice induced by STZ and a high-fat diet were subjected to PAS and Masson's staining. Glomerular mesangial cells (MCs) were treated with high glucose (HG) or normal glucose (NG). CCK-8 and EdU assays were performed to detect cell proliferation, and immunoblotting was conducted to analyze ECM deposition. ChIP-qPCR was performed on MCs to detect the binding of FOSL2 on the TGF-β1 promoter and a dual-luciferase assay to detect the impact of FOSL2 on the transcription of the TGF-β1 promoter.

Results: FOSL2 was elevated in the kidney tissues of DKD mice. Knockdown of FOSL2 reduced the mRNA expression of TGF-β1 to decrease the protein expression of GLUT1 and mTOR in the kidney tissues of DKD mice, and TGF-β1 reversed the effects caused by knockdown of FOSL2. The mTOR inhibitor Rapamycin alleviated kidney injury in the presence of FOSL2. Knockdown of FOSL2 inhibited the proliferation and improved ECM deposition of MCs, which were reversed by TGF-β1. Rapamycin and GLUT1 inhibitor BAY-876 reversed the promotion effect of FOSL2 on the proliferation of NG-MCs/HG-MCs and improved ECM deposition of MCs.

Conclusions: Our data demonstrated that FOSL2 accentuates DKD in mice by increasing TGF-β1-induced GLUT1/mTOR signaling.

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FOSL2 可激活 TGF-β1 介导的 GLUT1/mTOR 信号，从而促进糖尿病肾病的发生。

目的/简介：糖尿病肾病（DKD）是导致肾衰竭的主要原因。研究发现，狼疮性肾炎患者肾活检组织中的 FOS 样抗原 2（FOSL2）含量升高，但其与 DKD 的关系仍未解决。本研究旨在阐明FOSL2在DKD中的作用及其机制：方法：对 STZ 和高脂饮食诱导的 DKD 小鼠肾组织进行 PAS 和 Masson 染色。肾小球系膜细胞（MCs）经高葡萄糖（HG）或正常葡萄糖（NG）处理。用 CCK-8 和 EdU 检测细胞增殖，用免疫印迹分析 ECM 沉积。对 MCs 进行 ChIP-qPCR 检测 FOSL2 与 TGF-β1 启动子的结合情况，并用双荧光素酶检测 FOSL2 对 TGF-β1 启动子转录的影响：结果：FOSL2在DKD小鼠肾脏组织中升高。结果：FOSL2在DKD小鼠肾脏组织中升高，敲除FOSL2可降低TGF-β1的mRNA表达，从而降低DKD小鼠肾脏组织中GLUT1和mTOR的蛋白表达。mTOR抑制剂雷帕霉素能减轻FOSL2存在时的肾损伤。敲除 FOSL2 可抑制 MCs 的增殖并改善 ECM 的沉积，而 TGF-β1 可逆转这些影响。雷帕霉素和GLUT1抑制剂BAY-876逆转了FOSL2对NG-MCs/HG-MCs增殖的促进作用，并改善了MCs的ECM沉积：我们的数据表明，FOSL2 可通过增加 TGF-β1 诱导的 GLUT1/mTOR 信号转导来加重小鼠的 DKD。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Diabetes Investigation Medicine-Internal Medicine

自引率

9.40%

发文量

218

期刊介绍： Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).