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.

Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK

“…Rabbit antibodies directed against pNKCC1 (T212/217)/ pNKCC2 (T96/T101), pNKCC2 (S126), and pNCC (T58) have previously been described (10). Rabbit antibodies against AMPK-␣ and pACC1 (S79) have previously been described (33,50).…”

Kidney-specific genetic deletion of both AMPK α-subunits causes salt and water wasting

“…Although AMPK␣1 has been described as the more abundant catalytic subunit in the nephron segments of our interest (22,23), we have also conducted renal function studies, including sodium challenge experiments, in mice with genetic deletion of the AMPK ␣2-isoform. We did not find significant differences in renal function parameters between AMPK␣2 Ϫ/Ϫ mice and wild-type littermates, both under normal-or altered sodium intakes (data not shown).…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Two isoenzymes of ACC have been identified as ACC1 and ACC2, with a tissue-context expression manner, in which ACC2 has been elucidated as the major regulator of fatty acid oxidation in both cardiac and skeletal muscles, while similar function of ACC1 has been emphasized largely in renal tissue. Meanwhile, both isoenzymes during fatty acid oxidation share the functions in liver [144]. …”