Salt reabsorption is the major energy-requiring process in the kidney and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with a targeted deletion of the β1 subunit of AMPK (AMPK β^1-/- mice) had significantly increased urinary sodium excretion on a normal salt diet. This was associated with reduced expression of the β subunit of the epithelial sodium channel (ENaC) and increased sub-apical tubular expression of the kidney-specific Na-K-2Cl co-transporter NKCC2. AMPK β1^-/- mice fed a salt-deficient diet were able to conserve sodium but renin secretion increased 180% compared with controls. Cox-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 (ACC1-KI^S79A mice) were examined. ACC1-KI^S79A mice on a normal-salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, NCC and βENaC were similar to those in control mice. When placed on a salt-deficient diet, however, renin secretion and cortical expression of Cox-2 mRNA increased significantly in the ACC1-KI^S79A mice compared to controls. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.