As part of the assessment of metabolism nephrotoxicity of cadmium, we have studied the effect of cadmium chloride (CdCl2) on gluconeogenesis in isolated mouse and human renal proximal tubules. The dose-response experiments in vitro have shown that CdCl2 inhibits the use of lactate and glucose production in a dose-dependent fashion. Besides, the CdCl2 induced a significant decrease in cellular concentrations of ATP and the main compounds containing thiol groups such as coenzyme A and reduced glutathione. The enzymatic steps and 13C-NMR spectroscopy showed that CdCl2 produced in mouse and human kidney tubules respectively at concentrations of 10 and 100 μM, an inhibition of fluxes through lactate dehydrogenase and the entire gluconeogenic pathway. Our results are in favor of a direct inhibitory action of cadmium on enzymes involved in the gluconeogenic pathway. However, the decrease in intracellular ATP, glutathione and coenzyme A, would have a potentiating effect of this inhibition. Therefore, this study provides a biochemical basis for better understanding the cellular mechanisms of proximal tubular nephropathy occurring in humans following chronic exposure to cadmium.
