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

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.

The Na/K-ATPase Signaling: From Specific Ligands to General Reactive Oxygen Species.

The signaling function of the Na/K-ATPase has been established for 20 years and is widely accepted in the field, with many excellent reports and reviews not cited here. Even though there is debate about the underlying mechanism, the signaling function is unquestioned. This short review looks back at the evolution of Na/K-ATPase signaling, from stimulation by cardiotonic steroids (also known as digitalis-like substances) as specific ligands to stimulation by reactive oxygen species (ROS) in general. The interplay of cardiotonic steroids and ROS in Na/K-ATPase signaling forms a positive-feedback oxidant amplification loop that has been implicated in some pathophysiological conditions.

Author Correction: The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities.

Obesity has become a worldwide epidemic. We have previously reported that systemic administration of pNaKtide which targets the Na/K-ATPase oxidant amplification loop (NKAL) was able to decrease systemic oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play a central role in the development of obesity and its related comorbidities, we examined whether lentiviral-mediated adipocyte-specific expression of NaKtide, a peptide derived from the N domain of the alpha1 Na/K-ATPase subunit, could ameliorate the effects of the WD. C57BL6 mice were fed a WD, which activated Na/K-ATPase signaling in the adipocytes and induced an obese phenotype and caused an increase in plasma levels of leptin, IL-6 and TNFα. WD also decreased locomotor activity, expression of the D2 receptor and tyrosine hydroxylase in brain tissue, while markers of neurodegeneration and neuronal apoptosis were increased following the WD. Selective adipocyte expression of NaKtide in these mice fed a WD attenuated all of these changes including the brain biochemical alterations and behavioral adaptations. These data suggest that adipocyte derived cytokines play an essential role in the development of obesity induced by a WD and that targeting the adipocyte NKAL loop may serve as an effective therapeutic strategy.