ANP-stimulated Na secretion in the collecting duct prevents Na retention in the renal adaptation to acid load.

We have recently reported that type A intercalated cells of the collecting duct secrete Na by a mechanism coupling the basolateral type 1 Na-K-2Cl cotransporter with apical type 2 H-K-ATPase (HKA2) functioning under its Na/K exchange mode. The first aim of the present study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with Na retention. The second aim of the present study was to evaluate whether ANP-induced stimulation of Na secretion by type A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In oocytes expressing HKA2, cGMP, the second messenger of ANP, increased the membrane expression, activity, and Na-transporting rate of HKA2. Feeding mice with a NHCl-enriched diet increased urinary excretion of aldosterone and induced a transient Na retention that reversed within 3 days. At that time, expression of ANP mRNA in the collecting duct and urinary excretion of cGMP were increased. Reversion of Na retention was prevented by treatment with an inhibitor of ANP receptors and was absent in HKA2-null mice. In conclusion, paracrine stimulation of HKA2 by ANP is responsible for the escape of the Na-retaining effect of aldosterone during metabolic acidosis.