CADMIUM-INDUCED INHIBITION OF ADH-STIMULATED ION-TRANSPORT IN CULTURED KIDNEY-DERIVED EPITHELIAL-CELLS (A6)

An epithelial cell line (A6) derived from the distal tubule of toad ki dney, was used to study the effect of cadmium (Cd2+) on the increase i n active ion transport induced by antidiuretic hormone (ADH). Addition of Cd2+ (1mM) to the basolateral solution of A6 epithelia generated a n immediate and transient increase in active ion transport, measured a s short circuit current (SCC). This increase was not affected by prior addition of ADH. However, there was a distinct inhibition of ADH-indu ced stimulation of SCC in epithelia pre-treated with Cd2+. Since cAMP serves as an intracellular messenger for ADH by increasing the ion per meability of the apical membrane in A6 epithelial cells, the effects o f Cd2+ on enzymes involved in cAMP metabolism were measured. The resul ts showed that Cd2+ markedly inhibits cAMP production by inhibiting ad enylate cyclase (which had been stimulated with forskolin, magnesium o r a non-hydrolysed GTP-analog), indicating that Cd2+ inhibits the cata lytic subunit of adenylate cyclase. Furthermore, degradation of cAMP b y phosphodiesterase was not stimulated by Cd2+, also suggesting that t he mechanism by which Cd2+ inhibits the ADH-induced ion transport coul d be through inhibition of adenylate cyclase. Taken together, these re sults indicate that, in addition to the well-known toxic effect on the proximal tubule, Cd2+ could also have an effect on the distal part of the kidney, where the important hormonal regulation of salt and water homeostasis takes place.