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Title: Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK.
Austin Authors: Davies, Matthew R P ;Fraser, Scott A;Galic, Sandra;Choy, Suet-Wan ;Katerelos, Marina ;Gleich, Kurt;Kemp, Bruce E;Mount, Peter F ;Power, David Anthony
Affiliation: Department of Nephrology, University of Melbourne, Heidelberg, Victoria, Australia
Institute for Breathing and Sleep
St. Vincent's Institute, Fitzroy, Victoria, Australia
Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 7-May-2014
Publication information: American Journal of Physiology. Renal Physiology 2014; 307(1): F96-F106
Abstract: Enhanced tubular reabsorption of salt is important in the pathogenesis of obesity-related hypertension, but the mechanisms remain poorly defined. To identify changes in the regulation of salt transporters in the kidney, C57BL/6 mice were fed a 40% fat diet [high-fat diet (HFD)] or a 12% fat diet (control diet) for 14 wk. Compared with control diet-fed mice, HFD-fed mice had significantly greater elevations in weight, blood pressure, and serum insulin and leptin levels. When we examined Na(+) transporter expression, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) was unchanged in whole kidney and reduced in the cortex, Na(+)-Cl(-) cotransporter (NCC) and α-epithelial Na(+) channel (ENaC) and γ-ENaC were unchanged, and β-ENaC was reduced. Phosphorylation of NCC was unaltered. Activating phosphorylation of NKCC2 at S126 was increased 2.5-fold. Activation of STE-20/SPS1-related proline-alanine-rich protein kinase (SPAK)/oxidative stress responsive 1 kinase (OSR1) was increased in kidneys from HFD-fed mice, and enhanced phosphorylation of NKCC2 at T96/T101 was evident in the cortex. Increased activity of NKCC2 in vivo was confirmed with diuretic experiments. HFD-fed mice had reduced activating phosphorylation of AMP-activated protein kinase (AMPK) in the renal cortex. In vitro, activation of AMPK led to a reduction in phospho-SPAK/phospho-OSR1 in AMPK(+/+) murine embryonic fibroblasts (MEFs), but no effect was seen in AMPK(-/-) MEFs, indicating an AMPK-mediated effect. Activation of the with no lysine kinase/SPAK/OSR1 pathway with low-NaCl solution invoked a greater elevation in phospho-SPAK/phospho-OSR1 in AMPK(-/-) MEFs than in AMPK(+/+) MEFs, consistent with a negative regulatory effect of AMPK on SPAK/OSR1 phosphorylation. In conclusion, this study identifies increased phosphorylation of NKCC2 on S126 as a hitherto-unrecognized mediator of enhanced Na(+) reabsorption in obesity and identifies a new role for AMPK in regulating the activity of SPAK/OSR1.
DOI: 10.1152/ajprenal.00524.2013
Journal: American Journal of Physiology. Renal Physiology
Type: Journal Article
Subjects: AMP-activated protein kinase
Na+-K+-2Cl− cotransporter
STE-20/SPS1-related proline-alanine-rich protein kinase
oxidative stress responsive 1 kinase
AMP-Activated Protein Kinases.metabolism
Epithelial Sodium Channels.metabolism
Mice, Inbred C57BL
Protein-Serine-Threonine Kinases.metabolism
Sodium Chloride, Dietary.metabolism
Solute Carrier Family 12, Member 1.metabolism
Appears in Collections:Journal articles

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