Hyperglycaemia in CF adversely affects BK channel function critical for mucus clearance
- Charles D. Bengtson1,4,
- Michael D. Kim1,4,
- Abeer Anabtawi2,
- Jianghua He3,
- John S. Dennis1,
- Sara Miller1,
- Makoto Yoshida1,
- Nathalie Baumlin1 and
- Matthias Salathe1⇑
- 1Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, USA
- 2Department of Internal Medicine, Division of Endocrinology, Metabolism, and Genetics, University of Kansas Medical Center, Kansas City, USA
- 3Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA
- 4Contributed equally
- Dr Matthias Salathe, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., 4032 Delp, MS 1022, Kansas City, KS 66160, USA. E-mail: msalathe{at}kumc.edu.
Abstract
Large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel function is critical for adequate airway hydration and mucociliary function. In airway epithelia, BK function is regulated by its γ subunit leucine-rich repeat-containing protein 26 (LRRC26). Since patients with cystic fibrosis (CF)-related diabetes mellitus (CFRD) have worse lung function outcomes, this study determined the effects of hyperglycaemia on BK function in CF bronchial epithelial (CFBE) cells in vitro and evaluated the correlation between glycaemic excursions and mRNA expression of LRRC26 in the upper airways of CF and CFRD patients.
CFBE cells were re-differentiated at the air-liquid interface (ALI) in media containing either 5.5 mM or 12.5 mM glucose. BK activities were measured in Ussing chambers. Airway surface liquid (ASL) volumes were estimated by meniscus scanning and inflammatory marker expression was measured by quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). CF patients were assessed by 7 days of continuous glucose monitoring. LRRC26 mRNA expression was measured by qPCR from nasal cells obtained at the end of glucose monitoring.
BK currents were significantly decreased in CFBE cells cultured under high glucose. These cells revealed significantly lower ASL volumes and increased inflammation, including RAGE, compared to cells cultured in normal glucose. In vivo, nasal cell expression of LRRC26 mRNA was inversely correlated with hyperglycaemic excursions, consistent with the in vitro results.
Our findings demonstrate that hyperglycaemia induces inflammation and impairs BK channel function in CFBE cells in vitro. These data suggest that declining lung function in CFRD patients may be related to BK channel dysfunction.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Bengtson reports grants from Cystic Fibrosis Foundation, grants from NCATS, during the conduct of the study.
Conflict of interest: Dr. Kim reports grants from NIH, grants from Cystic Fibrosis Foundation, during the conduct of the study; grants from Flight Attendant Medical Research Institute, grants from James and Esther King Florida Biomedical Research Program, outside the submitted work.
Conflict of interest: Dr. Anabtawi reports grants from Cystic Fibrosis Foundation, grants from University of Kansas Pilot Support, during the conduct of the study.
Conflict of interest: Dr. He reports grants from Cystic Fibrosis Foundation, during the conduct of the study.
Conflict of interest: John S. Dennis has nothing to disclose.
Conflict of interest: Sara Miller has nothing to disclose.
Conflict of interest: Dr. Yoshida has nothing to disclose.
Conflict of interest: Nathalie Baumlin reports grants from NIH, grants from Cystic Fibrosis Foundation, during the conduct of the study; grants from Flight Attendant Medical Research Institute, grants from James and Esther King Florida Biomedical Research Program, outside the submitted work.
Conflict of interest: Dr. Salathe reports grants and personal fees from NIH, grants and personal fees from Cystic Fibrosis Foundation, during the conduct of the study; grants and personal fees from Arrowhead Pharmaceuticals, grants from COPD Foundation, grants from James and Esther King Florida Biomedical Research Program, grants and personal fees from Flight Attendant Medical Research Institute, outside the submitted work.
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- Received March 1, 2020.
- Accepted July 20, 2020.
- Copyright ©ERS 2020