TRPML1 agonist ML-SA5 mitigates uranium-induced nephrotoxicity via promoting lysosomal exocytosis

Uranium (U) released from U mining and spent nuclear fuel reprocessing in the nuclear industry, nuclear accidents and military activities as a primary environmental pollutant (e.g., drinking water pollution) is a threat to human health. Kidney is one of the main target organs for U accumulation, leading to nephrotoxicity mainly associated with the injuries in proximal tubular epithelial cells (PTECs). Transient receptor potential mucolipin 1 (TRPML1) is a novel therapeutic target for nephrotoxicity caused by acute or chronic U poisoning. We herein investigate the therapeutic efficacy of ML-SA5, a small molecule agonist of TRPML1, in U-induced nephrotoxicity in acute U intoxicated mice. We demonstrate that delayed treatment with ML-SA5 enhances U clearance from the kidneys via urine excretion by activating lysosomal exocytosis, and thereby attenuates U-induced kidney dysfunction and cell death/apoptosis of renal PTECs in acute U intoxicated mice. In addition, ML-SA5 promotes the nuclear translocation of transcription factor EB (TFEB) in renal PTECs in acute U intoxicated mice. Mechanistically, ML-SA5 triggers the TRPML1-mediated lysosomal calcium release and consequently induces TFEB activation in U-loaded renal PTECs-derived HK-2 cells. Moreover, knockdown of TRPML1 or TFEB abolishes the effects of ML-SA5 on the removal of intracellular U and reduction of the cellular injury/death in U-loaded HK-2 cells. Our findings indicate that pharmacological activation of TRPML1 is a promising therapeutic approach for the delayed treatment of U-induced nephrotoxicity via the activation of the positive feedback loop of TRPML1 and TFEB and consequent the induction of lysosomal exocytosis.