Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA.
FASEB J. 2018 Jun;32(6):3423-3433. doi: 10.1096/fj.201701316R. Epub 2018 Jan 22.
Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.
顺铂是一种广泛应用于癌症治疗的药物，会引起肾毒性或急性肾损伤（AKI），但其潜在机制尚不清楚，也没有有效的肾脏保护方法。成纤维细胞生长因子 21（FGF21）是一种内分泌因子，可调节葡萄糖摄取、代谢和能量消耗。然而，最近的研究也表明 FGF21 在致病条件下参与细胞应激反应。FGF21 在 AKI 中的作用和调节尚不清楚。在这里，我们发现 FGF21 在顺铂体外处理肾小管细胞和体内处理小鼠肾脏时显著诱导。Pifithrin（P53 的药理学抑制剂）抑制诱导反应，表明 P53 在 FGF21 诱导中起作用。在培养的肾小管细胞中，FGF21 的敲低加重了顺铂诱导的细胞凋亡，而重组 FGF21 的补充则具有保护作用。一致地，重组 FGF21 减轻了顺铂诱导的小鼠肾功能障碍、组织损伤和肾小管细胞凋亡。在机制上，FGF21 在顺铂处理期间抑制 P53 的诱导和激活。综上所述，这些结果表明 FGF21 在顺铂肾毒性期间被诱导以保护肾小管，重组 FGF21 可能具有治疗潜力。-李飞，刘钊，唐琛，蔡俊，董振芳。FGF21 在顺铂肾毒性中被诱导以保护肾小管免受损伤。
