FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice
Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast growth factors (FGFs) in renal pathophysiology. Here we reveal a previously unappreciated role of podocyte-secreted FGF4 in safeguarding renal function. FGF4 expression is downregulated in renal tissues from DKD patients and animal models, correlating with disease severity. Podocyte-specific deletion of Fgf4 exacerbated podocyte loss and accelerated DKD progression in mice. Conversely, treatment with recombinant FGF4 (rFGF4) improved glomerular filtration and reduced renal injury and fibrosis in diabetic male mice. These effects are primary mediated by activating the FGFR1-AMPK-FOXO1 signaling cascade in podocytes, which mitigates oxidative stress, suppresses apoptosis, and fosters podocyte survival. Notably, rFGF4 also restores the morphology and function of human podocytes exposed to high glucose. Our findings establish FGF4 as a critical regulator of podocyte homeostasis and a potential therapeutic target for DKD.
Authors
- Zhao Min (ORCID: https://orcid.org/0000-0001-6363-1158)
- Jian Sun (ORCID: https://orcid.org/0000-0002-1772-6786)
- Jing Zhou (ORCID: https://orcid.org/0000-0002-2475-7783)
- Beibin Pan (ORCID: https://orcid.org/0000-0001-8399-6920)
- Yali Du (ORCID: https://orcid.org/0000-0002-1817-0142)
- Yepeng Hu (ORCID: https://orcid.org/0009-0009-1681-503X)
- Jiaxin Lou (ORCID: https://orcid.org/0000-0001-6404-5142)
- Lingwei Jin (ORCID: https://orcid.org/0000-0003-0792-8517)
- Shuodan Ding
- Zhifeng Huang (ORCID: https://orcid.org/0000-0001-8269-6731)
- Qian Li (ORCID: https://orcid.org/0000-0003-0359-5604)
- Xinyi Wang (ORCID: https://orcid.org/0009-0002-6349-8013)
- Zhe Wang (ORCID: https://orcid.org/0000-0003-1120-030X)
- Xiaokun Li (ORCID: https://orcid.org/0000-0002-6556-6262)
- Shuxin Wang (ORCID: https://orcid.org/0000-0003-1609-5326)
- Xinwei Chen (ORCID: https://orcid.org/0000-0001-5443-0215)
- Chao Zheng (ORCID: https://orcid.org/0000-0002-2779-0255)
- Jie Zhou (ORCID: https://orcid.org/0009-0006-5755-9966)
- Jingjing Zhou (ORCID: https://orcid.org/0000-0001-5859-9827)
- Meiling Yu
Institutions
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University (CN)
- Taizhou First People's Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41467-025-65978-4
- Citations
- 1
- Primary Topic
- Chronic Kidney Disease and Diabetes
- Type
- article
- Field-Weighted Citation Impact
- 1.43
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- Medical and Health Research Project of Zhejiang Province
- Natural Science Foundation of Zhejiang Province