Transport of Tetraethylammonium in Renal Cortical Endosomes of Cadmium-Intoxicated Rats

Transport of Tetraethylammonium in Renal Cortical Endosomes of Cadmium-Intoxicated Rats

<P> Effects of cadmium (Cd) intoxication on renal endosomal accumulation of organic cations (OC<SUP>&#8290;</SUP>) were studied in rats using <SUP>14</SUP>C-tetraethylammnium (TEA) as a substrate. Cd intoxication was induced by s.c. injections of 2 mg Cd/kg/day for 2∼3 weeks. Renal cortical endosomes were isolated and the endosomal acidification (acridine orange fluorescence change) and TEA uptake (Millipore filtration technique) were assessed. The TEA uptake was an uphill transport mediated by H<SUP>&#8290;</SUP>/OC<SUP>&#8290;</SUP> antiporter driven by the pH gradient established by H<SUP>&#8290;</SUP>-ATPase. In endosomes of Cd-intoxicated rats, the ATP-dependent TEA uptake was markedly attenuated due to inhibition of endosomal acidification as well as H<SUP>&#8290;</SUP>/TEA antiport. In kinetic analysis of H<SUP>&#8290;</SUP>/TEA antiport, Vmax was reduced and Km was increased in the Cd group. Inhibition of H<SUP>&#8290;</SUP>/TEA antiport was also observed in normal endosomes directly exposed to free Cd (but not Cd-metallothionein complex, CdMt) <I>in vitro</I>. These data suggest that during chronic Cd exposure, free Cd ions liberated by lysosomal degradation of CdMt in proximal tubule cells may impair the endosomal accumulation of OC<SUP>&#8290;</SUP> by directly inhibiting the H<SUP>&#8290;</SUP>/OC<SUP>&#8290;</SUP> antiporter activity and indirectly by reducing the intravesicular acidification, the driving force for H<SUP>&#8290;</SUP>/OC<SUP>&#8290; </SUP>exchange.