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AMP-activated protein kinase (AMPK)-dependent and -independent pathways regulate hypoxic inhibition of transepithelial Na+ transport across human airway epithelial cells

Tan, CD; Smolenski, RT; Harhun, MI; Patel, HK; Ahmed, SG; Wanisch, K; Yáñez-Muñoz, RJ; Baines, DL (2012) AMP-activated protein kinase (AMPK)-dependent and -independent pathways regulate hypoxic inhibition of transepithelial Na+ transport across human airway epithelial cells. BRITISH JOURNAL OF PHARMACOLOGY, 167 (2). 368 - 382 (15). ISSN 0007-1188 https://doi.org/10.1111/j.1476-5381.2012.01993.x
SGUL Authors: Baines, Deborah Harhun, Maksym

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Abstract

Background and purpose Pulmonary transepithelial Na+ transport is reduced by hypoxia but in the airway the regulatory mechanisms remain unclear. We investigated the role of AMP activated protein kinase (AMPK) and reactive oxygen species (ROS) in the hypoxic regulation of apical amiloride-sensitive Na+ channels and basolateral Na+K+ATPase activity. Experimental approach H441 human airway epithelial cells were used to examine the effects of hypoxia on Na+ transport, AMP:ATP ratio and AMPK activity. Lentiviral constructs were used to modify cellular AMPK abundance and activity; pharmacological agents were used to modify cellular ROS. Key results AMPK was activated by exposure to 3% or 0.2% O2 for 60 minutes in cells grown in submerged culture or when fluid (0.1ml.cm−2) was added to the apical surface of cells grown at air-liquid-interface. Only exposure to 0.2% O2 activated AMPK in cells grown at air-liquid-interface. Activation of AMPK was associated with elevation of the cellular AMP:ATP ratio and activity of the upstream kinase LKB1. Hypoxia inhibited basolateral ouabain-sensitive Isc (Iouabain) and apical amiloride-sensitive Na+ conductance (GNa+). Modification of AMPK activity abrogated the effect of hypoxia on Iouabain (Na+K+ ATPase) but not apical GNa+. Scavenging of superoxide (O2−) and inhibition of NADPH oxidase prevented the effect of hypoxia on apical GNa+ (Epithelial Na+ channels, ENaC). Conclusions and Implications Hypoxia activates AMPK-dependent and -independent pathways in airway epithelial cells. Importantly, these pathways differentially regulate apical Na+ channels and basolateral Na+K+ATPase activity to decrease transepithelial Na+ transport. The finding that luminal fluid potentiated the effect of hypoxia and activated AMPK could have important consequences in lung disease conditions.

Item Type: Article
Additional Information: PubMed ID: 22509822
Keywords: AMP-Activated Protein Kinases, Biological Transport, Cell Line, Epithelial Cells, Gene Expression Regulation, Genetic Vectors, Humans, Lentivirus, Oxygen, Reactive Oxygen Species, Respiratory Mucosa, Sodium, Sodium-Potassium-Exchanging ATPase, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, PHARMACOLOGY & PHARMACY, AMPK, ROS, airway, epithelium, Na plus K plus ATPase, ENaC, ALTITUDE PULMONARY-EDEMA, SODIUM-CHANNELS, FLUID TRANSPORT, ALPHA-ENAC, LENTIVIRUS VECTOR, UPSTREAM KINASE, SKELETAL-MUSCLE, ION-TRANSPORT, A549 CELLS, IN-VITRO, AMPK, ROS, airway, epithelium, Na plus K plus ATPase, ENaC
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: BRITISH JOURNAL OF PHARMACOLOGY
ISSN: 0007-1188
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Dates:
DateEvent
1 September 2012Published
Web of Science ID: WOS:000307784100010
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URI: https://openaccess.sgul.ac.uk/id/eprint/103277
Publisher's version: https://doi.org/10.1111/j.1476-5381.2012.01993.x

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