In Vitro Evaluation of Cadmium‐Induced Phosphate Reabsorption Impairment

Cadmium (Cd) accumulates in the renal cortex and impairs phosphate reabsorption in the proximal tubules, leading to increased urinary phosphate excretion and hypophosphatemia. However, the molecular mechanisms underlying Cd-induced phosphate reabsorption dysfunction remain unclear. In this study, we developed an in vitro evaluation system using an immortalized rat proximal tubule cell line (NRK-52E) to assess cellular phosphate uptake and examine the effects of Cd. Exposure to subtoxic concentrations of Cd significantly decreased phosphate uptake, while neither cisplatin nor gentamicin did as nephrotoxicants. Cd exposure did not reduce Npt2a or Npt2c expression. Cd exposure caused a marked reduction in mitochondrial membrane potential, ATP production, and the expression of mitochondrial fusion-related factor OPA1 and respiratory chain components, along with prominent mitochondrial fragmentation. Treatment with inhibitors of OPA1 and the electron transport chain similarly impaired mitochondrial function and reduced phosphate uptake. These findings suggest that Cd-induced dysfunction of phosphate reabsorption involves OPA1-dependent mitochondrial fusion defects and mitochondrial dysfunction. This study provides new insights into the molecular mechanisms of Cd nephrotoxicity and demonstrates the potential of this in vitro model for evaluating reabsorption defects akin to Fanconi syndrome.