The 24p3 receptor is implicated in cadmium-induced distal tubule nephrotoxicity.

Accumulation of toxic metal cadmium (Cd) in the kidney is traditionally associated with proximal tubule (PT) toxicity, but the potential involvement of the distal tubule (DT) remains less explored. A previous study suggested a role of the 24p3 receptor (24p3R), expressed in the DT, in mediating cadmium-induced damage, particularly when PT function was compromised. A murine model (C57BL/6 J male mice) employing gentamicin (GM) to impair PT reabsorption was used to redirect cadmium-metallothionein (CdMT) complexes toward the distal segment. Here, we used the same model, confirming that DT-specific injury was evident following CdMT administration, including epithelial cell flattening, vacuolization, enhanced catalase activity, lipid peroxidation, and apoptotic cell death. Cd exposure increased 24p3R expression in the DT, supporting its involvement in metal uptake. Coadministration of 24p3, an endogenous ligand of 24p3R, with CdMT significantly reduced tissue Cd levels by 75 % and alleviated histological and biochemical markers of injury, suggesting that 24p3 competes with CdMT for receptor binding, limiting Cd entry and its downstream toxicity. Administration of 24p3 alone did not provoke structural or molecular alterations in renal tissue. The results identify 24p3R as a relevant pathway in DT-targeted cadmium nephrotoxicity and highlight the potential of 24p3-based strategies for mitigating renal injury due to exposure to potentially toxic elements.