Journal article
WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia
American journal of respiratory cell and molecular biology, Vol.67(4), pp.49-502
07/18/2022
DOI: 10.1165/rcmb.2022-0172OC
PMCID: PMC9564924
PMID: 35849656
Abstract
In cystic fibrosis (CF), reduced HCO32 secretion acidifies the airway surface liquid (ASL), and the acidic pH disrupts host defenses. Thus, understanding the control of ASL pH (pHASL) in CF may help identify novel targets and facilitate therapeutic development. In diverse epithelia, the WNK (with-no-lysine [K]) kinases coordinate HCO32 and Cl2 transport, but their functions in airway epithelia are poorly understood. Here, we tested the hypothesis that WNK kinases regulate CF pHASL. In primary cultures of differentiated human airway epithelia, inhibiting WNK kinases acutely increased both CF and non-CF pHASL. This response was HCO32 dependent and involved downstream SPAK/OSR1 (Ste20/SPS1-related prolinealanine-rich protein kinase/oxidative stress responsive 1 kinase). Importantly, WNK inhibition enhanced key host defenses otherwise impaired in CF. Human airway epithelia expressed two WNK isoforms in secretory cells and ionocytes, and knockdown of either WNK1 or WNK2 increased CF pHASL. WNK inhibition decreased Cl2 secretion and the response to bumetanide, an NKCC1 (sodium-potassium-chloride cotransporter 1) inhibitor. Surprisingly, bumetanide alone or basolateral Cl2 substitution also alkalinized CF pHASL. These data suggest that WNK kinases influence the balance between transepithelial Cl2 versus HCO32 secretion. Moreover, reducing basolateral Cl2 entry may increase HCO32 secretion and raise pHASL, thereby improving CF host defenses.
Details
- Title: Subtitle
- WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia
- Creators
- Tayyab Rehman - Roy J. and Lucille A. Carver College of MedicinePhilip H Karp - University of IowaAndrew L Thurman - Roy J. and Lucille A. Carver College of MedicineSteven E Mather - Roy J. and Lucille A. Carver College of MedicineAkansha Jain - Roy J. and Lucille A. Carver College of MedicineAshley L Cooney - Roy J. and Lucille A. Carver College of MedicinePatrick L Sinn - Roy J. and Lucille A. Carver College of MedicineAlejandro A Pezzulo - Roy J. and Lucille A. Carver College of MedicineMichael E Duffey - University at Buffalo, State University of New YorkMichael J Welsh - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.67(4), pp.49-502
- DOI
- 10.1165/rcmb.2022-0172OC
- PMID
- 35849656
- PMCID
- PMC9564924
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: HL091842; DOI: 10.13039/100000897, name: Cystic Fibrosis Foundation, award: Iowa RDP; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: K01HL140261; DOI: 10.13039/100000011, name: Howard Hughes Medical Institute
- Language
- English
- Date published
- 07/18/2022
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9984296206502771
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