FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice

Jie Zhou (), Shuxin Wang, Jiaxin Lou, Beibin Pan, Min Zhao, Qian Li, Jing Zhou, Yali Du, Shuodan Ding, Meiling Yu, Jingjing Zhou, Xinwei Chen, Lingwei Jin, Xinyi Wang, Yepeng Hu, Zhe Wang, Xiaokun Li, Chao Zheng (), Jian Sun () and Zhifeng Huang ()
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Jie Zhou: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Shuxin Wang: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Jiaxin Lou: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Beibin Pan: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Min Zhao: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Qian Li: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Jing Zhou: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Yali Du: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Shuodan Ding: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Meiling Yu: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Jingjing Zhou: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Xinwei Chen: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Lingwei Jin: Yuying Children’s Hospital of Wenzhou Medical University, Department of Nephrology, The Second Affiliated Hospital
Xinyi Wang: Huangyan Hospital of Wenzhou Medical University, Department of Endocrinology
Yepeng Hu: Zhejiang University, Department of Endocrinology, The Second Affiliated Hospital, School of Medicine
Zhe Wang: Zhejiang University, Department of Endocrinology, The Second Affiliated Hospital, School of Medicine
Xiaokun Li: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Chao Zheng: Zhejiang University, Department of Endocrinology, The Second Affiliated Hospital, School of Medicine
Jian Sun: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences
Zhifeng Huang: Wenzhou Medical University, State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65978-4

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