Occupational medicament-like dermatitis induced by trichloroethylene (TCE) is often linked to considerable renal impairment. However, the mechanisms underlying the renal damage remain poorly understood. The present study sought to elucidate the role of GSK3β in enhancing mitochondrial endoplasmic reticulum (ER) membrane tethering and calcium (Ca²⁺) exchange in the context of TCE sensitization-induced renal injury. Our results showed that GSK3β was localized within renal tubular epithelial cells and interacted with the IP3R1 calcium (Ca2+) channel complex at mitochondria-associated membranes (MAMs). TCE sensitization upregulated GSK3β activity and the expression of IP3R1 Ca2+ channel complex and its interactions, increased Ca²⁺ transfer from ER to mitochondria, Ca²⁺ overload, and apoptosis. The pharmacological inhibition of GSK3β disrupted the protein interaction between IP3R and the Ca²⁺ channel complex, leading to a decrease in Ca²⁺ exchange between the ER and mitochondria. This reduction resulted in a decrease in the mitochondrial Ca²⁺ concentration and an increase in the antiapoptotic ability of the cell. Coherent changes to renal function variables were also observed, demonstrating the functional relevance of the GSK3β pathway. Our results suggest that TCE sensitization damages renal tubular epithelial cells by promoting GSK3β-mediated crosstalk between the ER and mitochondria, identifying a key mechanism for TCE-induced renal injury. The findings from this study offer novel insights into the mechanisms of renal damage associated with TCE sensitization and lay down a foundation for the development of targeted preventive and therapeutic interventions.
Li et al. (Sun,) studied this question.