Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling

Liu, Jiang; Kennedy, David J.; Yan, Yanling; Shapiro, Joseph I.

doi:10.1155/2012/381320

Cited by 57 publications

(48 citation statements)

References 224 publications

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“…We and others have previously shown that activation of the sig- naling pool of Na-K-ATPase ␣1 by cardiotonic steroids is capable of protecting the heart from ischemic reperfusion injury (11,37,38,41). On the other hand, chronic stimulation of the Na-K-ATPase/Src receptor complex by either endogenous or infused cardiotonic steroids increases the generation of reactive oxygen species and induces cardiac hypertrophy and fibrosis in vivo (14,20,21,33,35). Furthermore, replacement of endogenous ouabain-resistant ␣1 with a ouabain-sensitive ␣1 mutant increases both cardiac hypertrophy and fibrosis in pressure-overload models (49).…”

Section: Discussionmentioning

confidence: 99%

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

Xie

Cui

et al. 2015

American Journal of Physiology-Cell Physiology

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Pase is a fundamental component of ion transport. Four ␣ isoforms of the Na-K-ATPase catalytic ␣ subunit are expressed in human cells. The ubiquitous Na-K-ATPase ␣1 was recently discovered to also mediate signal transduction through Src kinase. In contrast, ␣2 expression is limited to a few cell types including myocytes, where it is coupled to the Na ϩ /Ca 2ϩ exchanger. To test whether rat Na-KATPase ␣2 is capable of cellular signaling like its ␣1 counterpart in a recipient mammalian system, we used an ␣1 knockdown pig renal epithelial cell (PY-17) to create an ␣2-expressing cell line with no detectable level of ␣1 expression. These cells exhibited normal ouabain-sensitive ATPase, but failed to effectively regulate Src. In contrast to ␣1-expressing cells, ouabain did not stimulate Src kinase or downstream effectors such as ERK and Akt in ␣2 cells, although their signaling apparatus was intact as evidenced by EGF-mediated signal transduction. Additionally, ␣2 cells were unable to rescue caveolin-1. Unlike the NaKtide sequence derived from Na-K-ATPase ␣1, which downregulates basal Src activity, the corresponding ␣2 NaKtide was unable to inhibit Src in vitro. Finally, coimmunoprecipitation of cellular Src was diminished in ␣2 cells. These findings indicate that Na-K-ATPase ␣2 does not regulate Src and, therefore, may not serve the same role in signal transduction as ␣1. This further implies that the signaling mechanism of Na-K-ATPase is isoform specific, thereby supporting a model where ␣1 and ␣2 isoforms play distinct roles in mediating contraction and signaling in myocytes.rat Na-K-ATPase isoforms; Src tyrosine kinase; membrane transporters; ouabain; signal transduction THE NA-K-ATPASE, discovered in 1957 by Jens Skou, is a member of the P-type ATPase family and an integral membrane protein maintaining cellular ion homeostasis by pumping Na ϩ and K ϩ across the cell membrane (32). The protein consists of two noncovalently linked subunits, ␣ and ␤. The ␣-subunit contains the binding sites for substrates (e.g., ions and ATP) and ligands (e.g., ouabain) as it undergoes E1 and E2 conformational changes during a transport cycle. Four isoforms of the Na-K-ATPase ␣-subunit are expressed in humans. While ␣1 is expressed ubiquitously, ␣2 and ␣3 are primarily found in myocytes and neurons, respectively, and ␣4 is detected in sperm (3,4,31,45,50). Recent studies have revealed major differences in the physiological functions of each isoform. For example, the ␣2 isoform appears to possess the unique ability to regulate intracellular Ca 2ϩ levels in myocytes and coresides with the Na ϩ /Ca 2ϩ exchanger (5, 24). In addition, recent experiments using SWAP mice (ouabainsensitive ␣1 Na-K-ATPase mutant and ouabain-resistant ␣2 Na-K-ATPase mutant) suggest that the ␣2 isoform plays a more prominent role in calcium release in cardiac and smooth muscle myocytes than ␣1 (12).Over the last decade, we have also come to realize that the Na-K-ATPase may have many regulatory functions other than pumping ions across cell membranes. Studies fr...

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Section: Discussionmentioning

confidence: 99%

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

Xie

Cui

et al. 2015

American Journal of Physiology-Cell Physiology

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“…The effects of ROS on the Na/K-ATPase enzymatic activity have been well-studied [48]. Increases in ROS and/or RNS (reactive nitrogen species) cause oxidative modification of the Na/K- ATPase α and β subunits along with FXYD proteins.…”

Section: The Interplay Of Na/k-atpase and Ros - A Positive-feedback Omentioning

confidence: 99%

“…Impairment of the Na/K- ATPase/c-Src signaling, and/or carbonylation of the Na/K-ATPase abolishes this regulation and contributes to Dahl salt-sensitive hypertension [33, 48, 56, 60, 68, 69]. Functionally, carbonylation modification of the Na/K-ATPase is implicated in renal proximal tubular sodium handling and experimental salt sensitivity [reviewed in [18, 69]].…”

Section: The Positive-feedback Amplification Loop and Experimental DImentioning

confidence: 99%

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Liu

Lilly

Shapiro

2018

CPD

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Renal and cardiac function are greatly affected by chronic oxidative stress which can cause many pathophysiological states. The Na/K-ATPase is well-described as an ion pumping enzyme involved in maintaining cellular ion homeostasis; however, in the past two decades, extensive research has been done to understand the signaling function of the Na/K-ATPase and determine its role in physiological and pathophysiological states. Our lab has shown that the Na/K-ATPase signaling cascade can function as an amplifier of reactive oxygen species (ROS) which can be initiated by cardiotonic steroids or increases in ROS. Regulation of systemic oxidative stress by targeting Na/K-ATPase signaling mediated oxidant amplification improves 5/6th partial nephrectomy (PNx) mediated uremic cardiomyopathy, renal sodium handling, as well as ameliorates adipogenesis. This review will present this new concept of Na/K-ATPase signaling mediated oxidant amplification loop and its clinic implication.

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“…The assumptions necessary for this simple system of differential equations include (detailed R program shown in Appendix A):The Na/K-ATPase has a basal synthesis rate.ROS shift the Na/K-ATPase into the E2 state (as do CTS).There is a basal rate of ROS production from other sources.There is a link between Src phosphorylation and ROS production (oversimplifying the cascade, which we believe involves transactivation of the EGFR and other steps).There is a detoxification rate of ROS which is proportional to ROS concentration (an assumption that is at least partially true, based on the kinetics of superoxide dismutase and catalase).There is a relationship coupling ROS concentration to rates of endocytosis of the Na/K-ATPase [30]. …”

Section: Extension Of the Markov Chain To Define The Oxidant Amplimentioning

confidence: 99%

Quantum Modeling: A Bridge between the Pumping and Signaling Functions of Na/K-ATPase

Wang

Shapiro

2018

IJMS

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Although the signaling function of Na/K-ATPase has been studied for decades, the chasm between the pumping function and the signaling function of Na/K-ATPase is still an open issue. This article explores the relationship between ion pumping and signaling with attention to the amplification of oxidants through this signaling function. We specifically consider the Na/K-ATPase with respect to its signaling function as a superposition of different states described for its pumping function. We then examine how alterations in the relative amounts of these states could alter signaling through the Src-EGFR-ROS pathway. Using assumptions based on some experimental observations published by our laboratories and others, we develop some predictions regarding cellular oxidant stress.

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Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling

Cited by 57 publications

References 224 publications

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

Targeting Na/K-ATPase Signaling: A New Approach to Control Oxidative Stress

Quantum Modeling: A Bridge between the Pumping and Signaling Functions of Na/K-ATPase

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