Low dose ouabain stimulates Na K ATPase α1 subunit association with angiotensin II type 1 receptor in renal proximal tubule cells

Ketchem, Corey J.; Conner, Clayton; Murray, Rebecca; DuPlessis, Madalyn; Lederer, Eleanor; Wilkey, Daniel W.; Merchant, Michael L.; Khundmiri, Syed Jalal

doi:10.1016/j.bbamcr.2016.07.008

Cited by 17 publications

(18 citation statements)

References 42 publications

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“…These effects were prevented by the angiotensin II type 1 receptor (AT1R) blocker candesartan. The authors concluded that in renal proximal tubule cells, ouabain stimulates Na + ,K + -ATPase through an angiotensin/AT1R/Src/ERK1/2-dependent mechanism [ 93 ]. This signaling pathway is considered in more detail below.…”

Section: Evidence For Na + I K mentioning

confidence: 99%

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

et al. 2017

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Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na+ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na+i/K+i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death. It was also shown that CTS trigger diverse signaling cascades via conformational transitions of the Na+,K+-ATPase α-subunit that, in turn, results in the activation of membrane-associated non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase and the inositol 1,4,5-triphosphate receptor. These findings allowed researchers to propose that endogenous CTS might be considered as a novel class of steroid hormones. We focus our review on the analysis of the relative impact Na+i,K+i-mediated and -independent pathways in cellular responses evoked by CTS.

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Section: Evidence For Na + I K mentioning

confidence: 99%

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

et al. 2017

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“…The therapeutic window is narrow, however, and CTS have also been used as potent neurotoxins. CTS have been shown to stimulate signaling cascades through NKA at much lower concentrations than needed to impact ion transport 7–12 . These signaling functions are mediated by localized intracellular activation of Src-family kinases (SFK) and are independent of ion transport; because of the differences in dose response it is possible to activate NKA-mediated SFK signaling without altering Na/K homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Chen

Huang

Yang

et al. 2017

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Objective Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates pro-inflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce pro-inflammatory responses in primary murine and human macrophages. Approach and Results Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB, leading to pro-inflammatory cytokine (e.g. MCP-1, TNF-α, IL-1β and IL-6) production. By applying siRNA techniques as well as murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS or fully deficient in the scavenger receptor CD36 or TLR4 were resistant to ouabain-induced NF-κB activation, suggesting an indispensible role of these three receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex including Na/K-ATPase, CD36 and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C+CCR2+ monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. Conclusions CTS activate NF-κB leading to pro-inflammatory cytokine production in primary macrophages through a signaling complex including CD36, TLR4 and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases such as atherosclerosis.

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“…Low doses of Ouabain also reduce inflammatory cytokine production in LPS treated rats by blocking the nuclear translocation of NF-kB [ 20 ]. At low picomolar concentrations Ouabain promotes an interaction between the pump and the Angiotensin Type 1 Receptor (AT1R) [ 21 ]. It has also been demonstrated that AT1R directly interacts with ACE2 [ 22 ], the port of entry for the SARS and SARS-2 [ 23 ] coronaviruses.…”

Section: Resultsmentioning

confidence: 99%

Transcription-based drug repurposing for COVID-19

et al. 2020

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Highlights To date the Sever Acute Respiratory Syndrome coronavirus-2 (SARS-2) pandemic has taken over half a million lives. The devastating impact of the pandemic has led to a concerted effort in drug development. However, a vaccine is still at least many months away and novel drugs require years to reach the clinic. The pressing need for alternative strategies has generated interest in whether existing drugs may provide some benefits. Our work describes a drug repurposing strategy based on harnessing the gene expression changes associated with SARS infection of human lung epithelial cells. We show that the SARS infection signature is characterised by the up-regulation of viral defence genes and that drugs recapitulating this viral response are highly enriched for antiviral activity. Nine of our candidates have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.

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Low dose ouabain stimulates Na K ATPase α1 subunit association with angiotensin II type 1 receptor in renal proximal tubule cells

Cited by 17 publications

References 42 publications

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase

Transcription-based drug repurposing for COVID-19

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