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Int J Mol Sci. 2019 Jul 16;20(14). pii: E3495. doi: 10.3390/ijms20143495.

Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling.

Author information

1
Departments of Clinical & Translational Sciences, Biomedical Sciences, and Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA. yan@marshall.edu.
2
Departments of Clinical & Translational Sciences, Biomedical Sciences, and Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
3
Hebei Medical University, Shijiazhuang 50017, China.
4
Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.

Abstract

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

KEYWORDS:

Na/K-ATPase; metabolic syndrome; obesity; pressure-natriuresis curve; reactive oxygen species; salt-sensitive hypertension

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