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Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Feb 21; Vol. 21 (4). Date of Electronic Publication: 2020 Feb 21. - Publication Year :
- 2020
-
Abstract
- Alveolar edema, impaired alveolar fluid clearance, and elevated CO <subscript>2</subscript> 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 CO <subscript>2</subscript> 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 CO <subscript>2</subscript> 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 CO <subscript>2</subscript> 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 CO <subscript>2</subscript> levels, which may lead to the development of new therapeutic approaches for patients with ARDS and hypercapnia.
- Subjects :
- A549 Cells
Alveolar Epithelial Cells pathology
Animals
Endoplasmic Reticulum pathology
Humans
Hypercapnia pathology
Rats
Alveolar Epithelial Cells enzymology
Carbon Dioxide metabolism
Endoplasmic Reticulum enzymology
Hypercapnia enzymology
Protein Folding
Sodium-Potassium-Exchanging ATPase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32098115
- Full Text :
- https://doi.org/10.3390/ijms21041467