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Updated: Jun 7, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
FOSL2 activates TGF-β1-mediated GLUT1/mTOR signaling to promote diabetic kidney disease
Xuelin He1,2, Min Xia2, Guanghui Ying2
1Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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.
Insights
FOS-like antigen 2 (FOSL2) exacerbates diabetic kidney disease (DKD) by activating TGF-β1, GLUT1, and mTOR signaling pathways. Inhibiting these pathways may offer therapeutic strategies for DKD.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) is a leading cause of kidney failure.
- FOS-like antigen 2 (FOSL2) is elevated in lupus nephritis but its role in DKD is unknown.
Purpose of the Study:
- To investigate the role and mechanism of FOSL2 in diabetic kidney disease (DKD).
Main Methods:
- Studied kidney tissues from DKD mice and cultured mesangial cells (MCs).
- Assessed cell proliferation, extracellular matrix (ECM) deposition, and gene/protein expression.
- Utilized ChIP-qPCR and dual-luciferase assays to examine FOSL2's interaction with the TGF-β1 promoter.
Main Results:
- FOSL2 expression was increased in DKD mouse kidneys.
- FOSL2 knockdown reduced TGF-β1, GLUT1, and mTOR expression, improving MC proliferation and ECM deposition.
- TGF-β1 reversed the protective effects of FOSL2 knockdown.
- Rapamycin and a GLUT1 inhibitor ameliorated DKD-related kidney injury and MC dysfunction.
Conclusions:
- FOSL2 promotes DKD by enhancing TGF-β1-induced GLUT1/mTOR signaling.
- Targeting FOSL2, TGF-β1, GLUT1, or mTOR may be a therapeutic approach for DKD.
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