title: AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1.
abstract: 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 β1-subunit of AMPK (AMPK-β1(-/-) mice) had significantly increased urinary Na(+) excretion on a normal salt diet. This was associated with reduced expression of the β-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-β1(-/-) 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-KI(S79A) mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na(+)-Cl(-) cotransporter, and ENaC-β 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-KI(S79A) 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.
authors.affiliation: 1Kidney Laboratory, Institute for Breathing and Sleep, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Fraser
authors.forename: Suet-Wan
authors.initials: SW
authors.lastname: Choy
authors.forename: Núria M
authors.initials: NM
authors.lastname: Pastor-Soler
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Matthew R P
authors.initials: MR
authors.lastname: Davies
authors.forename: Natasha
authors.initials: N
authors.lastname: Cook
authors.forename: Marina
authors.initials: M
authors.lastname: Katerelos
authors.forename: Peter F
authors.initials: PF
authors.lastname: Mount
authors.forename: Kurt
authors.initials: K
authors.lastname: Gleich
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McRae
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dwyer
authors.forename: Bryce J W
authors.initials: BJ
authors.lastname: van Denderen
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hallows
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.forename: David A
authors.initials: DA
authors.lastname: Power
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D051379:Mice; D010766:Phosphorylation; D012083:Renin / Q000096:biosynthesis / Q000097:blood*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
chemical_list: D053503:Epithelial Sodium Channels; D017673:Sodium Chloride, Dietary; D012964:Sodium; D055372:AMP-Activated Protein Kinases; D012083:Renin; D000103:Acetyl-CoA Carboxylase
keywords: AMP-activated protein kinase; acetyl-CoA carboxylase 1; renin