期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 307, 期 1, 页码 F96-F106出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00524.2013
关键词
AMP-activated protein kinase; Na+-K+-2Cl(-) cotransporter; oxidative stress responsive 1 kinase; STE-20/SPS1-related proline-alanine-rich protein kinase
资金
- Australian National Health and Medical Research Council
- Victorian Government's Operational Infrastructure Support Program
- Medical Postgraduate Scholarship from the Australian National Health and Medical Research Council
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 alpha-epithelial Na+ channel (ENaC) and gamma-ENaC were unchanged, and beta-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据