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.