Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity.
Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity.
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DOI：
10.1038/s41467-023-39716-7
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发表时间：
2023-07-06
影响因子：
16.6
通讯作者：
Chen, Honghong
中科院分区：
文献类型：
--
作者：
Zhong, Dengqin;Wang, Ruiyun;Zhang, Hongjing;Wang, Mengmeng;Zhang, Xuxia;Chen, Honghong
铀（U）是一种众所周知的肾毒性物质，其在细胞毒性剂量的U暴露后在肾近端肾小管上皮细胞（PTECs）的溶酶体中形成沉淀物。然而，溶酶体在U的脱钙和解毒中的作用仍有待阐明。粘磷脂瞬时受体电位通道1（TRPML 1）是一种主要的溶酶体钙通道，调节溶酶体胞吐作用。我们在此证明，延迟给予特异性TRPML 1激动剂ML-SA 1显著降低了单剂量U中毒或多剂量U暴露的雄性小鼠肾PTEC中的U蓄积，减轻了肾近端肾小管损伤，增加了溶酶体的顶端胞吐作用并降低了溶酶体膜透化（LMP）。机制研究表明，ML-SA 1刺激细胞内U去除，并通过激活正TRPML 1-TFEB反馈环和随后的溶酶体胞吐作用和体外负载U的PTEC中的生物合成来减少U诱导的LMP和细胞死亡。总之，我们的研究表明，TRPML 1激活是一种有吸引力的治疗策略，用于治疗U诱导的肾毒性。溶酶体在铀（U）脱铀和解毒中的作用尚待阐明。在这里，作者证明TRPML 1激活是一种有吸引力的治疗策略，可以诱导溶酶体胞吐和生物合成，用于治疗U诱导的肾毒性。
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 Ca2+ 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. The roles of lysosomes in uranium (U) decorporation and detoxification remain to be elucidated. Here, the authors demonstrate that TRPML1 activation is an attractive therapeutic strategy to induce lysosomal exocytosis and biogenesis for the treatment of U-induced nephrotoxicity.
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影响因子：
16.6
作者：
Dong, Xian-ping;Shen, Dongbiao;Wang, Xiang;Dawson, Taylor;Li, Xinran;Zhang, Qi;Cheng, Xiping;Zhang, Yanling;Weisman, Lois S.;Delling, Markus;Xu, Haoxing
通讯作者：
Xu, Haoxing
影响因子：
3.4
作者：
Carmona, Asuncion;Porcaro, Francesco;Ortega, Richard
通讯作者：
Ortega, Richard
影响因子：
13.3
作者：
Aits, Sonja;Kricker, Jennifer;Jaattela, Marja
通讯作者：
Jaattela, Marja
DOI：
10.1016/j.nimb.2005.01.069
发表时间：
2005-04-01
影响因子：
1.3
作者：
Carrière, M;Gouget, B;Khodja, H
通讯作者：
Khodja, H
影响因子：
--
作者：
Toops KA;Lakkaraju A
通讯作者：
Lakkaraju A