Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, China; Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
Food Chem Toxicol. 2024 Feb;184:114378. doi: 10.1016/j.fct.2023.114378. Epub 2023 Dec 12.
Evidence suggests that ferroptosis participates in kidney injury. However, the role of ferroptosis in antimony (Sb) induced nephrotoxicity and the mechanism are unknown. Here, we demonstrated that Sb induced injury in renal tubular epithelial cells (RTECs) and ferroptosis. Inhibition of ferroptosis reduced RTECs injury. Besides, elimination of reactive oxygen species (ROS) alleviated ferroptosis and RTECs injury. Moreover, exposure to Sb not only increased the co-localization of glutathione peroxidase 4 (GPX4) and LAMP1, but also decreased the levels of MEF2D and LRRK2, while increased the levels of HSC70, HSP90, and LAMP2a. These findings suggest that Sb activates chaperone-mediated autophagy (CMA), enhances lysosomal transport and subsequent degradation of GPX4, ultimately leads to ferroptosis. Additionally, up-regulation of lysosomal cationic channel, TRPML1, mitigated RTECs injury and ferroptosis. Mechanistically, up-regulation of TRPML1 mitigated the changes in CMA-associated proteins induced by Sb, diminished the binding of HSC70, HSP90, and TRPML1 with LAMP2a. Furthermore, NAC restored the decreased TRPML1 level caused by Sb. In summary, deficiency of TRPML1, secondary to increased ROS induced by Sb, facilitates the CMA-dependent degradation of GPX4, thereby leading to ferroptosis and RTECs injury. These findings provide insights into the mechanism underlying Sb-induced nephrotoxicity and propose TRPML1 as a promising therapeutic target.
有证据表明，铁死亡参与了肾损伤。然而，铁死亡在锑（Sb）诱导的肾毒性中的作用及其机制尚不清楚。在这里，我们证明了 Sb 诱导肾小管上皮细胞（RTEC）损伤和铁死亡。铁死亡的抑制减少了 RTECs 的损伤。此外，消除活性氧（ROS）缓解了铁死亡和 RTECs 的损伤。此外，暴露于 Sb 不仅增加了谷胱甘肽过氧化物酶 4（GPX4）和 LAMP1 的共定位，而且降低了 MEF2D 和 LRRK2 的水平，同时增加了 HSC70、HSP90 和 LAMP2a 的水平。这些发现表明，Sb 激活伴侣介导的自噬（CMA），增强溶酶体转运和随后 GPX4 的降解，最终导致铁死亡。此外，溶酶体阳离子通道 TRPML1 的上调减轻了 RTECs 损伤和铁死亡。在机制上，TRPML1 的上调减轻了 Sb 诱导的 CMA 相关蛋白的变化，减少了 HSC70、HSP90 和 TRPML1 与 LAMP2a 的结合。此外，NAC 恢复了 Sb 引起的 TRPML1 水平降低。总之，由于 Sb 诱导的 ROS 增加，TRPML1 的缺乏促进了 CMA 依赖性的 GPX4 降解，从而导致铁死亡和 RTECs 损伤。这些发现为 Sb 诱导的肾毒性的机制提供了新的见解，并提出了 TRPML1 作为一个有前途的治疗靶点。
