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Mitochondrial fission-mediated podocyte dysfunction via CaMKII/Drp1 signaling pathways contributes to

Shuanghui Lu1, Yueping Qiu1, Yujia Chen2

  • 1Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.

Biochemical Pharmacology
|July 20, 2026
PubMed

Insights

Lenvatinib causes kidney injury by increasing mitochondrial fission in podocytes. Metformin, an antidiabetic drug, can reverse this damage by inhibiting mitochondrial fission, offering a potential treatment for lenvatinib-induced nephrotoxicity.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitors, like lenvatinib, can cause significant renal injury, primarily proteinuria, impacting patient outcomes.
  • Lenvatinib exhibits a high incidence of nephrotoxicity, necessitating a deeper understanding of its underlying mechanisms and potential therapeutic interventions.

Purpose of the Study:

  • To elucidate the mechanism by which lenvatinib induces renal injury.
  • To identify and evaluate potential therapeutic strategies to mitigate lenvatinib-induced nephrotoxicity.

Main Methods:

  • Investigated lenvatinib's effects on mouse kidneys, focusing on glomerular and tubular structures.
  • Examined the role of podocyte epithelial-mesenchymal transition (EMT)-like changes and mitochondrial dynamics.
  • Utilized zebrafish as a screening platform for mitochondrial fission inhibitors and validated findings in vitro and in vivo.

Main Results:

  • Lenvatinib induced dose-dependent glomerular injury, characterized by proteinuria, focal segmental glomerulosclerosis, and podocyte loss, without significant tubular damage.
  • Glomerular injury was linked to podocyte EMT-like changes driven by increased mitochondrial fission via CaMKII-mediated Drp1 (Ser616) phosphorylation.
  • Metformin and melatonin demonstrated significant protective effects against lenvatinib-induced renal edema in zebrafish; metformin alleviated nephrotoxicity by suppressing Drp1 (Ser616) phosphorylation in podocytes.

Conclusions:

  • Increased mitochondrial fission through the CaMKII/Drp1 signaling pathway in podocytes is a key contributor to lenvatinib-induced kidney injury.
  • Metformin emerges as a promising and clinically viable therapeutic option for managing lenvatinib-induced renal injury.
Keywords:
CaMKII/Drp1LenvatinibMitochondrial fissionPodocyteRenal injury

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