Luteolin prevents axitinib-induced kidney damage in mice

Axitinib, a tyrosine kinase inhibitor (TKI) with antiangiogenic effects, is used in anticancer therapy. Axitinib can cause dose-limiting adverse reactions such as proteinuria and renal function impairment, but the mechanisms remain unclear. This study aims to elucidate the mechanism of axitinib-induced proteinuria and potential intervention strategies. We employed C57BL/6 mice as the primary subjects, administering axitinib (50 mg/kg/day) for 1 week, along with luteolin (100 mg/kg/day) to observe its protective effects. Our findings demonstrated that axitinib induced elevated urinary protein and creatinine levels in C57BL/6 mice, resulting in pathological changes in glomeruli, including thickened glomerular basement membrane (GBM), podocyte foot process effacement, disruption of the filtration slit diaphragm structure, and collagen deposition. Axitinib significantly reduced the protein expression of podocyte filtration barrier core functional proteins (nephrin, podocin, and podocalyxin) and upregulated transient receptor potential channel 6 (TRPC6) expression. Pharmacological inhibition of TRPC6 with SAR7334 alleviated axitinib-induced downregulation of these core proteins. Luteolin exerts a protective effect and demonstrates a stable binding conformation with TRPC6 along with high binding affinity. Our results elucidate that axitinib induces podocyte filtration barrier core protein loss, foot process effacement, glomerulosclerosis, and proteinuria through upregulation of TRPC6 protein expression. Additionally, naturally derived luteolin serves as a potential intervention strategy, providing a theoretical basis for the clinical prevention and treatment of nephrotoxicity caused by axitinib and other TKIs.