Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, PR China.
Nat Commun. 2023 Jul 6;14(1):3997. doi: 10.1038/s41467-023-39716-7.
Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.
铀 (U) 是一种众所周知的肾毒性物质，在细胞毒性剂量暴露后，会在肾近端小管上皮细胞 (PTEC) 的溶酶体中形成沉淀物。然而，溶酶体在 U 解毒和解毒中的作用仍有待阐明。粘脂蛋白瞬时受体电位通道 1 (TRPML1) 是一种主要的溶酶体 Ca 通道，调节溶酶体胞吐作用。本文证明，特异性 TRPML1 激动剂 ML-SA1 的延迟给药可显著减少雄性小鼠单次 U 染毒或多次 U 暴露后肾脏中的 U 蓄积，减轻肾近端小管损伤，增加溶酶体顶泌作用，并减少溶酶体膜通透性 (LMP) 在肾 PTECs 中。机制研究表明，ML-SA1 通过激活正向 TRPML1-TFEB 反馈环，随后在体外负载 U 的 PTEC 中进行溶酶体胞吐作用和生物发生，刺激细胞内 U 去除，并减少 U 诱导的 LMP 和细胞死亡。总之，我们的研究表明，TRPML1 激活是治疗 U 诱导的肾毒性的一种有吸引力的治疗策略。
