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Am J Physiol Renal Physiol
2010 Jul 01;2991:F167-77. doi: 10.1152/ajprenal.00162.2010.
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Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells.
Li H
,
Thali RF
,
Smolak C
,
Gong F
,
Alzamora R
,
Wallimann T
,
Scholz R
,
Pastor-Soler NM
,
Neumann D
,
Hallows KR
.
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The metabolic sensor AMP-activated protein kinase (AMPK) regulates several transport proteins, potentially coupling transport activity to cellular stress and energy levels. The creatine transporter (CRT; SLC6A8) mediates creatine uptake into several cell types, including kidney epithelial cells, where it has been proposed that CRT is important for reclamation of filtered creatine, a process critical for total body creatine homeostasis. Creatine and phosphocreatine provide an intracellular, high-energy phosphate-buffering system essential for maintaining ATP supply in tissues with high energy demands. To test our hypothesis that CRT is regulated by AMPK in the kidney, we examined CRT and AMPK distribution in the kidney and the regulation of CRT by AMPK in cells. By immunofluorescence staining, we detected CRT at the apical pole in a polarized mouse S3 proximal tubule cell line and in native rat kidney proximal tubules, a distribution overlapping with AMPK. Two-electrode voltage-clamp (TEV) measurements of Na(+)-dependent creatine uptake into CRT-expressing Xenopus laevis oocytes demonstrated that AMPK inhibited CRT via a reduction in its Michaelis-Menten V(max) parameter. [(14)C]creatine uptake and apical surface biotinylation measurements in polarized S3 cells demonstrated parallel reductions in creatine influx and CRT apical membrane expression after AMPK activation with the AMP-mimetic compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside. In oocyte TEV experiments, rapamycin and the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate (ZMP) inhibited CRT currents, but there was no additive inhibition of CRT by ZMP, suggesting that AMPK may inhibit CRT indirectly via the mammalian target of rapamycin pathway. We conclude that AMPK inhibits apical membrane CRT expression in kidney proximal tubule cells, which could be important in reducing cellular energy expenditure and unnecessary creatine reabsorption under conditions of local and whole body metabolic stress.
Almaça,
AMPK controls epithelial Na(+) channels through Nedd4-2 and causes an epithelial phenotype when mutated.
2009, Pubmed
Almaça,
AMPK controls epithelial Na(+) channels through Nedd4-2 and causes an epithelial phenotype when mutated.
2009,
Pubmed
Bens,
Corticosteroid-dependent sodium transport in a novel immortalized mouse collecting duct principal cell line.
1999,
Pubmed
Bessman,
The creatine-creatine phosphate energy shuttle.
1985,
Pubmed
Bhalla,
AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2.
2006,
Pubmed
,
Xenbase
Brown,
Antigen retrieval in cryostat tissue sections and cultured cells by treatment with sodium dodecyl sulfate (SDS).
1996,
Pubmed
Carattino,
Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells.
2005,
Pubmed
,
Xenbase
Chen,
Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.
2004,
Pubmed
Chen,
Activation of the ERK pathway and atypical protein kinase C isoforms in exercise- and aminoimidazole-4-carboxamide-1-beta-D-riboside (AICAR)-stimulated glucose transport.
2002,
Pubmed
Dai,
Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Fraser,
Regulation of the renal-specific Na+-K+-2Cl- co-transporter NKCC2 by AMP-activated protein kinase (AMPK).
2007,
Pubmed
,
Xenbase
García-Delgado,
Ontogeny up-regulates renal Na(+)/Cl(-)/creatine transporter in rat.
2007,
Pubmed
García-Delgado,
Creatine transport in brush-border membrane vesicles isolated from rat kidney cortex.
2001,
Pubmed
Gong,
Vacuolar H+-ATPase apical accumulation in kidney intercalated cells is regulated by PKA and AMP-activated protein kinase.
2010,
Pubmed
Guerrero,
Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase.
1997,
Pubmed
,
Xenbase
Guimbal,
A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression.
1993,
Pubmed
Hallows,
Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation.
2006,
Pubmed
Hallows,
Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells.
2003,
Pubmed
,
Xenbase
Hallows,
Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase.
2000,
Pubmed
,
Xenbase
Hallows,
Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells.
2003,
Pubmed
,
Xenbase
Hallows,
Emerging role of AMP-activated protein kinase in coupling membrane transport to cellular metabolism.
2005,
Pubmed
Hallows,
AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells.
2009,
Pubmed
Hallows,
Regulation of epithelial Na+ transport by soluble adenylyl cyclase in kidney collecting duct cells.
2009,
Pubmed
,
Xenbase
Hardie,
The AMP-activated protein kinase pathway--new players upstream and downstream.
2004,
Pubmed
Hardie,
AMP-activated protein kinase--development of the energy sensor concept.
2006,
Pubmed
Huang,
In vivo stimulation of AMP-activated protein kinase enhanced tubuloglomerular feedback but reduced tubular sodium transport during high dietary NaCl intake.
2010,
Pubmed
Hwang,
Metabolic profiling of kidney and urine in rats with lithium-induced nephrogenic diabetes insipidus by (1)H-NMR-based metabonomics.
2010,
Pubmed
Kaunitz,
Inhibition of gentamicin uptake into cultured mouse proximal tubule epithelial cells by L-lysine.
1993,
Pubmed
Klein,
Inhibition of the KCa3.1 channels by AMP-activated protein kinase in human airway epithelial cells.
2009,
Pubmed
Mazzochi,
Interaction of epithelial ion channels with the actin-based cytoskeleton.
2006,
Pubmed
Mount,
Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177.
2005,
Pubmed
Neumann,
A molecular approach to the concerted action of kinases involved in energy homoeostasis.
2003,
Pubmed
Park,
A metabonomic study on the biochemical effects of doxorubicin in rats using (1)H-NMR spectroscopy.
2009,
Pubmed
Peral,
Human, rat and chicken small intestinal Na+ - Cl- -creatine transporter: functional, molecular characterization and localization.
2002,
Pubmed
Peral,
Na(+)/Cl(-)/creatine transporter activity and expression in rat brain synaptosomes.
2010,
Pubmed
Schlattner,
Mitochondrial creatine kinase in human health and disease.
2006,
Pubmed
Shaw,
The LKB1 tumor suppressor negatively regulates mTOR signaling.
2004,
Pubmed
Shojaiefard,
Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3.
2005,
Pubmed
,
Xenbase
Shojaiefard,
Stimulation of the creatine transporter SLC6A8 by the protein kinase mTOR.
2006,
Pubmed
,
Xenbase
Sopjani,
Down-regulation of Na+-coupled glutamate transporter EAAT3 and EAAT4 by AMP-activated protein kinase.
2010,
Pubmed
,
Xenbase
Stead,
Is it time to reevaluate methyl balance in humans?
2006,
Pubmed
Stockler,
Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology.
2007,
Pubmed
Straumann,
Effects of N-linked glycosylation on the creatine transporter.
2006,
Pubmed
Strutz-Seebohm,
PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8.
2007,
Pubmed
,
Xenbase
Walker,
Creatine: biosynthesis, regulation, and function.
1979,
Pubmed
Wallimann,
Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis.
1992,
Pubmed
Woollhead,
Phenformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) activation of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells.
2005,
Pubmed
Wyss,
Creatine and creatinine metabolism.
2000,
Pubmed
Yang,
Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions.
2010,
Pubmed
