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Open AccessArticle

Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells

1
Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany
2
The Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
3
Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
4
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
5
Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
6
Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1467; https://doi.org/10.3390/ijms21041467
Received: 3 February 2020 / Revised: 16 February 2020 / Accepted: 17 February 2020 / Published: 21 February 2020
(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)
Alveolar edema, impaired alveolar fluid clearance, and elevated CO2 levels (hypercapnia) are hallmarks of the acute respiratory distress syndrome (ARDS). This study investigated how hypercapnia affects maturation of the Na,K-ATPase (NKA), a key membrane transporter, and a cell adhesion molecule involved in the resolution of alveolar edema in the endoplasmic reticulum (ER). Exposure of human alveolar epithelial cells to elevated CO2 concentrations caused a significant retention of NKA-β in the ER and, thus, decreased levels of the transporter in the Golgi apparatus. These effects were associated with a marked reduction of the plasma membrane (PM) abundance of the NKA-α/β complex as well as a decreased total and ouabain-sensitive ATPase activity. Furthermore, our study revealed that the ER-retained NKA-β subunits were only partially assembled with NKA α-subunits, which suggests that hypercapnia modifies the ER folding environment. Moreover, we observed that elevated CO2 levels decreased intracellular ATP production and increased ER protein and, particularly, NKA-β oxidation. Treatment with α-ketoglutaric acid (α-KG), which is a metabolite that has been shown to increase ATP levels and rescue mitochondrial function in hypercapnia-exposed cells, attenuated the deleterious effects of elevated CO2 concentrations and restored NKA PM abundance and function. Taken together, our findings provide new insights into the regulation of NKA in alveolar epithelial cells by elevated CO2 levels, which may lead to the development of new therapeutic approaches for patients with ARDS and hypercapnia. View Full-Text
Keywords: carbon dioxide; hypercapnia; Na,K-ATPase; endoplasmic reticulum; sodium transport; protein oxidation; alveolar epithelium carbon dioxide; hypercapnia; Na,K-ATPase; endoplasmic reticulum; sodium transport; protein oxidation; alveolar epithelium
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Kryvenko, V.; Wessendorf, M.; Morty, R.E.; Herold, S.; Seeger, W.; Vagin, O.; Dada, L.A.; Sznajder, J.I.; Vadász, I. Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells. Int. J. Mol. Sci. 2020, 21, 1467.

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