RETRACTED ARTICLE: The Na/K-ATPase Oxidant Amplification Loop Regulates Aging

Sodhi, Komal; Nichols, Alexandra; Mallick, Amrita; Klug, Rebecca L.; Liu, Jiang; Wang, Xiaoliang; Srikanthan, Krithika; Goguet-Rubio, Perrine; Nawab, Athar; Pratt, Rebecca; Lilly, Megan N.; Sanabria, Juan; Xie, Zijian; Abraham, Nader G.; Shapiro, Joseph I.

doi:10.1038/s41598-018-26768-9

Cited by 29 publications

(51 citation statements)

References 78 publications

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“…3T3-L1 pre-adipocytes and MSC-derived adipocytes were plated in 24-well plates and exposed to UTs, IS or p-cresol, with or without subsequent pNaKtide treatment as described above. A Vybrant MTT Cell Proliferation Assay Kit (Invitrogen) was used and manufacturer’s protocol was followed [ 30 ]. The assessment of MTT assay will determine the optimal concentration of UTs that is effective in inducing phenotypic alterations in 3T3-L1 pre-adipocytes, while eliminating the use of possible cytotoxic or ineffective concentrations.…”

Section: Methodsmentioning

confidence: 99%

Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

Bartlett

Miller

Thiesfeldt

et al. 2018

IJMS

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Background: Oxidant stress plays a key role in the development of chronic kidney disease (CKD). Experimental CKD leads to accumulation of uremic toxins (UT) in the circulation resulting in increased ROS production, which in turn, is known to activate the Na/K-ATPase/ROS amplification loop. Studies in a murine model of obesity have shown that increased oxidative stress in plasma is due to increased ROS and cytokine production from dysfunctional adipocytes. Therefore, we hypothesized that adipocytes exposed to UTs will activate the Na/K-ATPase oxidant amplification loop causing redox imbalance and phenotypic alterations in adipocytes. We also aimed to demonstrate that the Na/K-ATPase signaling antagonist, pNaKtide, attenuates these pathophysiological consequences. Methods: In the first set of experiments, 3T3-L1 murine pre-adipocytes were treated with varying concentrations of UTs, indoxyl sulfate (IS) (50, 100 and 250 µM) and p-cresol (50, 100 and 200 µM), with or without pNaKtide (0.7 µM) for five days in adipogenic media, followed by Oil Red O staining to study adipogenesis. RT-PCR analysis was performed to study expression of adipogenic, apoptotic and inflammatory markers, while DHE staining evaluated the superoxide levels in UT treated cells. In a second set of experiments, visceral fat was obtained from the West Virginian population. MSCs were isolated and cultured in adipogenic media for 14 days, which was treated with indoxyl sulfate (0, 25, 50 and 100 µM) with or without pNaKtide (1 µM). MSC-derived adipocytes were evaluated for morphological and molecular analysis of the above markers. Results: Our results demonstrated that 3T3-L1 cells and MSCs-derived adipocytes, treated with UTs, exhibited a significant decrease in adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification loop. The treatment with pNaKtide in 3T3-L1 cells and MSC-derived adipocytes negated the effects of UTs and restored cellular redox in adipocytes. We noted a varying effect of pNaKtide, in adipocytes treated with UTs, on inflammatory markers, adipogenic marker and superoxide levels in 3T3-L1 cells and MSC-derived adipocytes. Conclusions: This study demonstrates for the first time that the Na/K-ATPase/ROS amplification loop activated by elevated levels of UTs has varying effect on phenotypic alterations in adipocytes in various in vitro models. Thus, we propose that, if proven in humans, inhibition of Na/K-ATPase amplification of oxidant stress in CKD patients may ultimately be a novel way to combat adipocyte dysfunction and metabolic imbalance in these patients.

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Section: Methodsmentioning

confidence: 99%

Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

Bartlett

Miller

Thiesfeldt

et al. 2018

IJMS

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“…Taken together, it indicates that the oxidant amplification loop is important for the development of uremic cardiomyopathy (Figure 2). Moreover, this oxidant amplification loop has also been demonstrated to affect other pathophysiological alterations in other types of animal models including the Western diet, obesity, ageing, steatohepatitis, atherosclerosis, and adipogenesis [113][114][115]. In pre-adipocyte 3T3-L1 cells and MSC-derived adipocytes, uremic toxin indoxyl sulfate and p-cresol sulfate can stimulate the Na/K-ATPase signaling and the oxidant amplification loop [116], suggesting that this oxidant amplification loop is not limited to one cell type.…”

Section: The Na/k-atpase Signaling and Oxidative Stress In Uremic Carmentioning

confidence: 99%

The Redox-Sensitive Na/K-ATPase Signaling in Uremic Cardiomyopathy

Liu

Nie

Chaudhry

et al. 2020

IJMS

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In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.

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“…The Na/K-ATPase signaling cascade has been extensively studied due to its recently elucidated role as a scaffolding and signaling protein. Studies over the last two decades, since the emergence of the Xie Model of Na/K-ATPase signaling, have demonstrated that activation of this signaling pathway is pivotal in exacerbating oxidative stress in several disease models [8,9,17,18]. While several subunits of Na/K-ATPase have been dissected and known to be involved in its distinct ion pumping function, the α1 subunit of Na/K-ATPase signaling primarily causes its structural modulation leading to the activation of membrane-bound tyrosine kinase protein, Src [19,20].…”

Section: Mechanistic Insights Into Na/k-atpase Oxidant Amplification mentioning

confidence: 99%

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

Pratt

Lakhani

Zehra

et al. 2019

IJMS

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Obesity is a multifaceted pathophysiological condition that has been associated with lipid accumulation, adipocyte dysfunction, impaired mitochondrial biogenesis and an altered metabolic profile. Redox imbalance and excessive release of inflammatory mediators have been intricately linked in obesity-associated phenotypes. Hence, understanding the mechanisms of redox signaling pathways and molecular targets exacerbating oxidative stress is crucial in improving health outcomes. The activation of Na/K-ATPase/Src signaling, and its downstream pathways, by reactive oxygen species (ROS) has been recently implicated in obesity and subsequent nonalcoholic steatohepatitis (NASH), which causes further production of ROS creating an oxidant amplification loop. Apart from that, numerous studies have also characterized antioxidant properties of heme oxygenase 1 (HO-1), which is suppressed in an obese state. The induction of HO-1 restores cellular redox processes, which contributes to inhibition of the toxic milieu. The novelty of these independent mechanisms presents a unique opportunity to unravel their potential as molecular targets for redox regulation in obesity and NASH. The attenuation of oxidative stress, by understanding the underlying molecular mechanisms and associated mediators, with a targeted treatment modality may provide for improved therapeutic options to combat clinical disorders.

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RETRACTED ARTICLE: The Na/K-ATPase Oxidant Amplification Loop Regulates Aging

Cited by 29 publications

References 78 publications

Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

Uremic Toxins Activates Na/K-ATPase Oxidant Amplification Loop Causing Phenotypic Changes in Adipocytes in In Vitro Models

The Redox-Sensitive Na/K-ATPase Signaling in Uremic Cardiomyopathy

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

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