Hyperphosphorylation of Na-pump contributes to defective renal dopamine response in old rats

Dopamine D1-like receptor activation causes phosphorylation and inhibition of Na,K-ATPase (Na-pump) activity in the proximal tubules, which is associated with an increase in sodium excretion. It has been shown that dopamine and SKF 38393, a D1-like receptor agonist, caused inhibition of Na,K-ATPase activity in the proximal tubules of adult (6 mo) but not of old (24 mo) Fischer 344 rats. The present study demonstrated that SKF 38393 and PDBu, a phorbol ester and protein kinase C (PKC) activator, increased phosphorylation of the alpha(1)-subunit of Na,K-ATPase in adult but not in old rats. In adult rats, SKF 38393-mediated phosphorylation was antagonized by SCH 23390, a D1-like receptor antagonist. Similarly, Na,K-ATPase activity was inhibited by SKF 38393 and PDBu in adult but not in old rats. The basal activity of Na,K-ATPase was decreased and the basal phosphorylation state of the enzyme was increased in old compared with adult rats. Basal activity of PKC was higher in old compared with adult rats, and SKF 38393 and PDBu stimulated PKC activity in adult but not in old rats. The conclusion is that the failure of D1-like receptor agonist and phorbol ester to stimulate PKC and inhibit Na,K-ATPase activity in old rats is due, at least in part, to the higher basal PKC activity and Na,K-ATPase phosphorylation in old compared with adult rats.