AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1.

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 targeted deletion of the beta 1-subunit of AMPK (AMPK-beta 1(-/-) mice) had significantly increased urinary Na+ excretion on a normal salt diet. This was associated with reduced expression of the beta-subunit of the epithelial Na+ channel (ENaC) and increased subapical tubular expression of kidney-specific Na+-K+-2Cl(-) cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-beta 1(-/-) mice fed a salt-deficient diet were able to conserve Na+, but renin secretion increased 180% compared with control mice. Cyclooxygenase-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-knockin (KI)(S79A) mice] were examined. ACC1-KIS79A mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na+-Cl- cotransporter, and ENaC-beta were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KIS79A mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.