FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease
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...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Journal of Diabetes Investigation |
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| Online Access: | https://doi.org/10.1111/jdi.14360 |
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| author | Xuelin He Min Xia Guanghui Ying Qien He Zhaogui Chen Li Liu Qiao Zhang Jianxin Cai |
| author_facet | Xuelin He Min Xia Guanghui Ying Qien He Zhaogui Chen Li Liu Qiao Zhang Jianxin Cai |
| author_sort | Xuelin He |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ce9e38ac984847b89c1499a00e2158f7 |
| institution | Kabale University |
| issn | 2040-1116 2040-1124 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Investigation |
| spelling | doaj-art-ce9e38ac984847b89c1499a00e2158f72025-02-01T10:02:01ZengWileyJournal of Diabetes Investigation2040-11162040-11242025-02-0116218720310.1111/jdi.14360FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney diseaseXuelin He0Min Xia1Guanghui Ying2Qien He3Zhaogui Chen4Li Liu5Qiao Zhang6Jianxin Cai7Kidney Disease Center, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang ChinaDepartment of Nephrology Beilun People's Hospital Ningbo Zhejiang ChinaDepartment of Nephrology Beilun People's Hospital Ningbo Zhejiang ChinaDepartment of Nephrology Beilun People's Hospital Ningbo Zhejiang ChinaDepartment of Nephrology Beilun People's Hospital Ningbo Zhejiang ChinaDepartment of Library The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou Zhejiang ChinaZhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang ChinaDepartment of Pediatric Wuhan Hospital of Traditional Chinese Medicine Wuhan Hubei ChinaABSTRACT 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.https://doi.org/10.1111/jdi.14360Diabetic kidney diseaseFOSL2GLUT1/mTOR signaling |
| spellingShingle | Xuelin He Min Xia Guanghui Ying Qien He Zhaogui Chen Li Liu Qiao Zhang Jianxin Cai FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease Journal of Diabetes Investigation Diabetic kidney disease FOSL2 GLUT1/mTOR signaling |
| title | FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease |
| title_full | FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease |
| title_fullStr | FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease |
| title_full_unstemmed | FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease |
| title_short | FOSL2 activates TGF‐β1‐mediated GLUT1/mTOR signaling to promote diabetic kidney disease |
| title_sort | fosl2 activates tgf β1 mediated glut1 mtor signaling to promote diabetic kidney disease |
| topic | Diabetic kidney disease FOSL2 GLUT1/mTOR signaling |
| url | https://doi.org/10.1111/jdi.14360 |
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