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

Int J Mol Sci. 2019 Jul 16;20(14):3495. doi: 10.3390/ijms20143495.


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.

MeSH terms

  • Animals
  • Hypertension / etiology
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Kidney / metabolism
  • MAP Kinase Signaling System*
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Obesity / genetics
  • Obesity / metabolism*
  • Protein Carbonylation
  • Reactive Oxygen Species / metabolism
  • Sodium / blood
  • Sodium / urine
  • Sodium Chloride, Dietary / adverse effects
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • src-Family Kinases / metabolism


  • Reactive Oxygen Species
  • Sodium Chloride, Dietary
  • Sodium
  • src-Family Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Sodium-Potassium-Exchanging ATPase