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|Title:||Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK.|
|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:||Kidney Laboratory, Institute for Breathing and Sleep, University of Melbourne, Heidelberg, Victoria, Australia; Department of Nephrology, University of Melbourne, Heidelberg, Victoria, Australia; Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia; and.|
St. Vincent's Institute, Fitzroy, Victoria, Australia.
Kidney Laboratory, Institute for Breathing and Sleep, University of Melbourne, Heidelberg, Victoria, Australia;
Kidney Laboratory, Institute for Breathing and Sleep, University of Melbourne, Heidelberg, Victoria, Australia; Department of Nephrology, University of Melbourne, Heidelberg, Victoria, Australia; Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia; and David.Power@austin.org.au.
|Citation:||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.|
|Internal ID Number:||24808538|
|Subjects:||AMP-activated protein kinase|
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
Sodium Chloride, Dietary.metabolism
Solute Carrier Family 12, Member 1.metabolism
|Appears in Collections:||Journal articles|
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