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• W2004706099 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." @default.
• W2004706099 created "2016-06-24" @default.
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• W2004706099 date "2014-07-01" @default.
• W2004706099 modified "2023-09-26" @default.
• W2004706099 title "Novel mechanisms of Na⁺ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK" @default.
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• W2004706099 doi "https://doi.org/10.1152/ajprenal.00524.2013" @default.
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• W2004706099 hasPublicationYear "2014" @default.
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