Mitochondrial fission-mediated podocyte dysfunction via CaMKII/Drp1 signaling pathways contributes to lenvatinib-induced renal injury.

Abstract

The adverse effects of VEGF signaling pathway inhibitors, notably renal injury manifested as proteinuria, critically impair clinical outcomes and health-related quality of life, with lenvatinib inducing the highest incidence. This study aims to investigate the mechanism of lenvatinib-induced renal injury, and then to explore potential therapeutic strategies. We identified that lenvatinib induced severe glomerular injury, characterized by proteinuria, focal segmental glomerulosclerosis, and loss of podocytes in a dose-dependent manner, but no apparent tubular injury in the mouse kidney. Further studies revealed that lenvatinib-induced glomerular injury was associated with the epithelial-mesenchymal transition-like changes of podocytes, driven by increased mitochondrial fission through CaMKⅡ-mediated upregulation of Drp1 phosphorylation at Ser616. Using zebrafish as an in vivo screening platform, we further identified several mitochondrial fission inhibitors-including metformin, andrographolide, melatonin, berberine, and mdivi-1-that exhibited protective effects against lenvatinib-induced renal edema, with metformin and melatonin showing the most pronounced efficacy. Metformin, an antidiabetic drug, was further demonstrated to alleviate lenvatinib-induced nephrotoxicity both in vitro and in vivo by reversing the epithelial-mesenchymal transition-like changes of podocytes through the suppression of Drp1(Ser616) phosphorylation. These findings provide the first evidence suggesting that increased mitochondrial fission via CaMKII/Drp1 signaling pathways in podocytes contributes to lenvatinib-induced kidney injury, and identify metformin as a clinically viable treatment option for lenvatinib-induced renal injury.