S-adenosyl-L-homocysteine hydrolase regulates aldosterone-induced Na+ transport

Aldosterone-induced Na+ reabsorption, in part, is regulated by a critical m ethyl esterification; however, the signal transduction pathway regulating t his methylation remains unclear. The A6 cell line was used as a model epith elia to investigate regulation of aldosterone-induced Na+ transport by S-ad enosyl-L-homocysteine hydrolase (SAHHase), the only enzyme in vertebrates k nown to catabolize S-adenosyl-L-homocysteine (SAH), an end product inhibito r of methyl esterification, Sodium reabsorption was decreased within 2 h by 3-deazaadenosine, a competitive inhibitor of SAHHase, with a half inhibito ry concentration between 40 and 50 mu M. Aldosterone increased SAH cataboli sm by activating SAHHase. Increased SAH catabolism was associated with a co ncomitant increase in S-adenosylmethionine catabolism, Moreover, SAH decrea sed substrate methylation. Antisense oligonucleotide complementary to SAHHa se mRNA decreased SAHHase activity and Na+ current by approximately 50%. Ov erexpression of SAHHase increased SAHHase activity and dependent substrate methyl esterification, Whereas basal Na+ current was not affected by overex pression of SAHHase, aldosterone-induced current in SAHHase-overexpressing cells was significantly potentiated. These results demonstrate that aldoste rone induction of SAHHase activity is necessary for a concomitant relief of the methylation reaction from end product inhibition by SAH and the subseq uent increase in Na+ reabsorption. Thus, regulation of SAHHase activity is a control point for aldosterone signal transduction, but SAHHase is not an aldosterone-induced protein.