TY - JOUR
T1 - The Effects of the Anti-aging Protein Klotho on Mucociliary Clearance
AU - Garth, Jaleesa
AU - Easter, Molly
AU - Skylar Harris, Elex
AU - Sailland, Juliette
AU - Kuenzi, Lisa
AU - Chung, Samuel
AU - Dennis, John S.
AU - Baumlin, Nathalie
AU - Adewale, Adegboyega T.
AU - Rowe, Steven M.
AU - King, Gwendalyn
AU - Faul, Christian
AU - Barnes, Jarrod W.
AU - Salathe, Matthias
AU - Krick, Stefanie
N1 - Funding Information:
Funding. This work was supported by the Flight Attendant Medical Research Institute (YFAC152003; to SK and CIA160011 to MS) and the Cystic Fibrosis Foundation (CFF P30 DK072482 and CFF Rowe19RO; to SK; SALATH16G0 to MS), the NIA (R03AG059994 to SK), and the NIH (R01HL128714 to CF and R01HL133240, R01HL139365 to MS), and the James and Esther King Florida Biomedical Research Program (5JK02 to MS).
Publisher Copyright:
© Copyright © 2020 Garth, Easter, Skylar Harris, Sailland, Kuenzi, Chung, Dennis, Baumlin, Adewale, Rowe, King, Faul, Barnes, Salathe and Krick.
PY - 2020/1/24
Y1 - 2020/1/24
N2 - α-klotho (KL) is an anti-aging protein and has been shown to exert anti-inflammatory and anti-oxidative effects in the lung and pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The current study investigated the direct effect of KL on the bronchial epithelium in regards to mucociliary clearance parameters. Primary human bronchial and murine tracheal epithelial cells, cultured, and differentiated at the air liquid interface (ALI), were treated with recombinant KL or infected with a lentiviral vector expressing KL. Airway surface liquid (ASL) volume, airway ion channel activities, and expression levels were analyzed. These experiments were paired with ex vivo analyses of mucociliary clearance in murine tracheas from klotho deficient mice and their wild type littermates. Our results showed that klotho deficiency led to impaired mucociliary clearance with a reduction in ASL volume in vitro and ex vivo. Overexpression or exogenous KL increased ASL volume, which was paralleled by increased activation of the large-conductance, Ca2+-activated, voltage-dependent potassium channel (BK) without effect on the cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, KL overexpression downregulated IL-8 levels and attenuated TGF-β-mediated downregulation of LRRC26, the γ subunit of BK, necessary for its function in non-excitable cells. In summary, we show that KL regulates mucociliary function by increasing ASL volume in the airways possibly due to underlying BK activation. The KL mediated BK channel activation may be a potentially important target to design therapeutic strategies in inflammatory airway diseases when ASL volume is decreased.
AB - α-klotho (KL) is an anti-aging protein and has been shown to exert anti-inflammatory and anti-oxidative effects in the lung and pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The current study investigated the direct effect of KL on the bronchial epithelium in regards to mucociliary clearance parameters. Primary human bronchial and murine tracheal epithelial cells, cultured, and differentiated at the air liquid interface (ALI), were treated with recombinant KL or infected with a lentiviral vector expressing KL. Airway surface liquid (ASL) volume, airway ion channel activities, and expression levels were analyzed. These experiments were paired with ex vivo analyses of mucociliary clearance in murine tracheas from klotho deficient mice and their wild type littermates. Our results showed that klotho deficiency led to impaired mucociliary clearance with a reduction in ASL volume in vitro and ex vivo. Overexpression or exogenous KL increased ASL volume, which was paralleled by increased activation of the large-conductance, Ca2+-activated, voltage-dependent potassium channel (BK) without effect on the cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, KL overexpression downregulated IL-8 levels and attenuated TGF-β-mediated downregulation of LRRC26, the γ subunit of BK, necessary for its function in non-excitable cells. In summary, we show that KL regulates mucociliary function by increasing ASL volume in the airways possibly due to underlying BK activation. The KL mediated BK channel activation may be a potentially important target to design therapeutic strategies in inflammatory airway diseases when ASL volume is decreased.
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U2 - 10.3389/fmed.2019.00339
DO - 10.3389/fmed.2019.00339
M3 - Article
AN - SCOPUS:85079153731
VL - 6
JO - Frontiers in Medicine
JF - Frontiers in Medicine
SN - 2296-858X
M1 - 339
ER -