ArticleThe Journal of clinical investigation2008
AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis.
Article in The Journal of clinical investigation, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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Who cites it
115 citing papers in PubMed, 167 citations in OpenAlex.
- Hypercapnia enhances airway smooth muscle contractility via STIM1-dependent Ca2+ signaling.JCI insight · 2026Article
- Hypercapnia Effects on Lung Function.Comprehensive Physiology · 2026Review
- The ribosomal landscape in influenza A virus infection: from molecular mechanisms to clinical relevance.European respiratory review : an official journal of the European Respiratory Society · 2026Review
- Long-term DNA methylation changes induced by age and elevated COSkeletal muscle · 2025Article
- Hypercapnia as a Double-Edged Modulator of Innate Immunity and Alveolar Epithelial Repair: A PRISMA-ScR Scoping Review.International journal of molecular sciences · 2025Article
- Sensing molecular carbon dioxide: a translational focus for respiratory disease.Physiological reviews · 2025Review
- Rapamycin improves satellite cells' autophagy and muscle regeneration during hypercapnia.JCI insight · 2025Article
- AMPK and glucose deprivation exert an isoform-specific effect on the expression of NaJournal of muscle research and cell motility · 2024Article
- Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus.International journal of molecular sciences · 2024Review
- Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS).Respiratory research · 2024Review
- Alveolar-capillary endocytosis and trafficking in acute lung injury and acute respiratory distress syndrome.Frontiers in immunology · 2024Review
- Neutrophil extracellular traps trigger alveolar epithelial cell necroptosis through the cGAS-STING pathway during acute lung injury in mice.International journal of biological sciences · 2024Article
- Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.Physiological genomics · 2023Article
- Impact of Arterial CORespiratory care · 2023Article
- The Tissue Response to Hypoxia: How Therapeutic Carbon Dioxide Moves the Response toward Homeostasis and Away from Instability.International journal of molecular sciences · 2023Review
- Hypercapnia alters stroma-derived Wnt production to limit β-catenin signaling and proliferation in AT2 cells.JCI insight · 2023Article
- Article
- Extracorporeal Membrane Oxygenation for Refractory Asthma Exacerbations With Respiratory Failure.Chest · 2023Observational
- Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol.Frontiers in immunology · 2023Article
- Hypercapnia in COPD: Causes, Consequences, and Therapy.Journal of clinical medicine · 2022Review
55 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 5 countries.
Funding
Abstract
Hypercapnia (elevated CO(2) levels) occurs as a consequence of poor alveolar ventilation and impairs alveolar fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating CO(2)-induced Na,K-ATPase endocytosis in alveolar epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated CO(2) levels caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator of metabolic homeostasis. Activation of AMPK was mediated by a CO(2)-triggered increase in intracellular Ca(2+) concentration and Ca(2+)/calmodulin-dependent kinase kinase-beta (CaMKK-beta). Chelating intracellular Ca(2+) or abrogating CaMKK-beta function by gene silencing or chemical inhibition prevented the CO(2)-induced AMPK activation in AECs. Activation of AMPK or overexpression of constitutively active AMPK was sufficient to activate PKC-zeta and promote Na,K-ATPase endocytosis. Inhibition or downregulation of AMPK via adenoviral delivery of dominant-negative AMPK-alpha(1) prevented CO(2)-induced Na,K-ATPase endocytosis. The hypercapnia effects were independent of intracellular ROS. Exposure of rats to hypercapnia for up to 7 days caused a sustained decrease in AFR. Pretreatment with a beta-adrenergic agonist, isoproterenol, or a cAMP analog ameliorated the hypercapnia-induced impairment of AFR. Accordingly, we provide evidence that elevated CO(2) levels are sensed by AECs and that AMPK mediates CO(2)-induced Na,K-ATPase endocytosis and alveolar epithelial dysfunction, which can be prevented with beta-adrenergic agonists and cAMP.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.