226: FGF4 protects podocytes in diabetic kidney disease

Wang S et al., Nat Commun - This study shows that podocyte-derived FGF4 is reduced in DKD and that recombinant FGF4 preserves podocyte survival and glomerular function in diabetic models via FGFR1-AMPK-FOXO1 signaling. Key terms: FGF4, FGFR1, podocyte, AMPK-FOXO1, diabetic kidney disease.

Study Highlights:
FGF4 expression is downregulated in kidneys from DKD patients and diabetic mouse models and localizes predominantly to podocytes. Podocyte-specific deletion of Fgf4 worsened albuminuria, reduced GFR, increased oxidative stress and podocyte loss in diabetic mice. Systemic treatment with a non-mitogenic recombinant FGF4 improved glucose in db/db mice, lowered UACR and BUN, reduced fibrosis, ROS and apoptosis, and restored podocyte markers in both T1D and T2D models. The protective effects of rFGF4 require podocyte FGFR1 and downstream AMPK-FOXO1 activity, as Fgfr1, Ampk, or Foxo1 podocyte knockouts abolished rFGF4 benefits. rFGF4 also reversed high glucose–induced injury and promoted nuclear FOXO1 in human podocytes and isolated human glomeruli

Conclusion:
FGF4 is a podocyte-derived regulator that promotes podocyte survival and mitigates DKD through FGFR1-mediated activation of the AMPK-FOXO1 axis, supporting rFGF4 as a potential therapeutic approach for diabetic kidney disease

Music:
Enjoy the music based on this article at the end of the episode.

First author:
Wang S

Journal:
Nat Commun

DOI:
10.1038/s41467-025-65978-4

Reference:
Wang S, Lou J, Pan B, Zhao M, Li Q, Zhou J, et al. FGF4-FGFR1 signaling promotes podocyte survival and glomerular function to ameliorate diabetic kidney disease in male mice. Nat Commun. 2025;16:10430. https://doi.org/10.1038/s41467-025-65978-4

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the scientific content of the transcript, focusing on: DKD context and podocyte injury; FGF4 downregulation and podocyte-specific Fgf4 knockout effects; rFGF4 therapeutic effects in DKD mouse models; FGFR1-AMPK-FOXO1 signaling; human cell data; safety considerations; interactions with losartan and SGLT2 inhibit
- transcript topics: DKD and podocyte injury; FGF4 as a podocyte-protective factor; Podocyte-specific Fgf4 knockout model (PKO); Recombinant FGF4 therapy in DKD (db/db and STZ models); FGFR1-AMPK-FOXO1 signaling axis; Human podocyte/glomerulus data and translational relevance

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- DKD downregulates FGF4 in podocytes and correlates with disease severity
- Podocyte-specific deletion of Fgf4 worsens DKD outcomes (lower GFR, higher albuminuria, histological damage)
- Recombinant FGF4 (rFGF4) protects against DKD in two mouse models (db/db and STZ), reducing kidney injury and fibrosis
- FGFR1-AMPK-FOXO1 signaling mediates rFGF4's protective effects in podocytes
- Protection by rFGF4 is non-glycemic and can occur even when blood glucose remains high
- Human relevance: rFGF4 reverses injury in human podocytes and human glomeruli under high glucose

QC result: Pass.