Journal Article

Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity

Zhong, Dengqin, Wang, Ruiyun, Chen, Honghong, Zhang, Hongjing, Zhang, Xuxia, Wang, Mengmeng

2023

Overview

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 2+ 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/109 / 13/2 / 13/51 / 14 / 14/19 / 14/28 / 14/63 / 631/154/556 / 692/308/153 / 692/700/3160 / Animals / Biosynthesis / Calcium - metabolism / Calcium ions / Cell death / Cytotoxicity / Detoxification / Epithelial cells / Epithelium / Exocytosis / Feedback loops / Humanities and Social Sciences / Injury prevention / Ions / Kidneys / Lysosomes / Lysosomes - metabolism / Male / Mice / multidisciplinary / Precipitates / Science / Science (multidisciplinary) / Transient Receptor Potential Channels - metabolism / Transient receptor potential proteins / Uranium / Uranium - metabolism / Uranium - toxicity