WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia
| العنوان: | WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia |
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| المؤلفون: | Tayyab Rehman, Philip H. Karp, Andrew L. Thurman, Steven E. Mather, Akansha Jain, Ashley L. Cooney, Patrick L. Sinn, Alejandro A. Pezzulo, Michael E. Duffey, Michael J. Welsh |
| المصدر: | American Journal of Respiratory Cell and Molecular Biology. 67:491-502 |
| بيانات النشر: | American Thoracic Society, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Pulmonary and Respiratory Medicine, Alanine, Cystic Fibrosis, Proline, Sodium-Potassium-Chloride Symporters, Clinical Biochemistry, Cell Biology, Hydrogen-Ion Concentration, Protein Serine-Threonine Kinases, WNK Lysine-Deficient Protein Kinase 1, Humans, Protein Isoforms, Protein Kinases, Molecular Biology, Bumetanide |
| الوصف: | In cystic fibrosis (CF), reduced HCOsub3/subsup-/supsecretion acidifies the airway surface liquid (ASL), and the acidic pH disrupts host defenses. Thus, understanding the control of ASL pH (pHsubASL/sub) in CF may help identify novel targets and facilitate therapeutic development. In diverse epithelia, the WNK (with-no-lysine [K]) kinases coordinate HCOsub3/subsup-/supand Clsup-/suptransport, but their functions in airway epithelia are poorly understood. Here, we tested the hypothesis that WNK kinases regulate CF pHsubASL/sub. In primary cultures of differentiated human airway epithelia, inhibiting WNK kinases acutely increased both CF and non-CF pHsubASL/sub. This response was HCOsub3/subsup-/supdependent and involved downstream SPAK/OSR1 (Ste20/SPS1-related proline-alanine-rich protein kinase/oxidative stress responsive 1 kinase). Importantly, WNK inhibition enhanced key host defenses otherwise impaired in CF. Human airway epithelia expressed twoiWNK/iisoforms in secretory cells and ionocytes, and knockdown of eitheriWNK1/ioriWNK2/iincreased CF pHsubASL/sub. WNK inhibition decreased Clsup-/supsecretion and the response to bumetanide, an NKCC1 (sodium-potassium-chloride cotransporter 1) inhibitor. Surprisingly, bumetanide alone or basolateral Clsup-/supsubstitution also alkalinized CF pHsubASL/sub. These data suggest that WNK kinases influence the balance between transepithelial Clsup-/supversus HCOsub3/subsup-/supsecretion. Moreover, reducing basolateral Clsup-/supentry may increase HCOsub3/subsup-/supsecretion and raise pHsubASL/sub, thereby improving CF host defenses. |
| تدمد: | 1535-4989 1044-1549 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d8b1f9bffca58e51ad561baf9bb5a3bTest https://doi.org/10.1165/rcmb.2022-0172ocTest |
| رقم الانضمام: | edsair.doi.dedup.....4d8b1f9bffca58e51ad561baf9bb5a3b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15354989 10441549 |
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