The Effects of the Anti-aging Protein Klotho on Mucociliary Clearance

被引:10
作者
Garth, Jaleesa [1 ]
Easter, Molly [1 ]
Skylar Harris, Elex [1 ,2 ]
Sailland, Juliette [3 ]
Kuenzi, Lisa [3 ]
Chung, Samuel [3 ,4 ]
Dennis, John S. [3 ,4 ]
Baumlin, Nathalie [3 ,4 ]
Adewale, Adegboyega T. [4 ]
Rowe, Steven M. [1 ,2 ]
King, Gwendalyn [5 ]
Faul, Christian [6 ]
Barnes, Jarrod W. [1 ,2 ]
Salathe, Matthias [3 ,4 ]
Krick, Stefanie [1 ,2 ]
机构
[1] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA
[3] Univ Miami, Miller Sch Med, Dept Med, Div Pulm Allergy Crit Care & Sleep Med, Miami, FL 33136 USA
[4] Univ Kansas, Med Ctr, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Kansas City, KS 66103 USA
[5] Creighton Univ, Dept Biol, Omaha, NE 68178 USA
[6] Univ Alabama Birmingham, Dept Med, Div Nephrol, Birmingham, AL 35294 USA
关键词
klotho; mucociliary clearance; TGF-beta; airway surface liquid volume; calcium activated potassium channels; CONDUCTANCE REGULATOR DYSFUNCTION; AIRWAY SURFACE DEHYDRATION; CYSTIC-FIBROSIS; EPITHELIAL-CELLS; CHANNEL; REDUCTION; MEMBRANE; LEADS; GENE; PH;
D O I
10.3389/fmed.2019.00339
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
alpha-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-beta-mediated downregulation of LRRC26, the gamma 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.
引用
收藏
页数:8
相关论文
共 50 条
[41]   THE ROLE OF α-KLOTHO PROTEIN IN AGING [J].
Sokolowska, Ewa ;
Milczarek, Ryszard ;
Hallmann, Anna ;
Klimek, Jerzy .
POSTEPY BIOLOGII KOMORKI, 2013, 40 (01) :101-120
[42]   Anti-inflammatories and mucociliary clearance therapies in the age of CFTR modulators [J].
Perrem, Lucy ;
Ratjen, Felix .
PEDIATRIC PULMONOLOGY, 2019, 54 :S46-S55
[43]   HMG-CoA reductase inhibition improves anti-aging klotho protein expression and arteriosclerosis in rats with chronic inhibition of nitric oxide synthesis [J].
Kuwahara, Noriko ;
Sasaki, Susumu ;
Kobara, Miyuki ;
Nakata, Tetsuo ;
Tatsumi, Tetsuya ;
Irie, Hidekazu ;
Narumiya, Hiromichi ;
Hatta, Tsuguru ;
Takeda, Kazuo ;
Matsubara, Hiroaki ;
Hushiki, Shinji .
INTERNATIONAL JOURNAL OF CARDIOLOGY, 2008, 123 (02) :84-90
[44]   The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway [J].
Zhou, Shuyan ;
Hum, Jacob ;
Taskintuna, Kaan ;
Olaya, Stephanie ;
Steinman, Jeremy ;
Ma, Junfeng ;
Golestaneh, Nady .
ANTIOXIDANTS, 2023, 12 (02)
[45]   Anti-aging gene Klotho ameliorates diabetic nephropathy in mice by inhibiting FGF2 signaling pathway [J].
Dong, Q-L ;
Zhao, X-H ;
Wang, Q. ;
Zhang, L-P ;
Yan, X-H ;
Wang, X-M ;
Li, Z-J ;
Sun, Y. .
JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS, 2020, 34 (04) :1369-1377
[46]   Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway [J].
Hsu, Shih-Che ;
Huang, Shih-Ming ;
Lin, Shih-Hua ;
Ka, Shuk-Man ;
Chen, Ann ;
Shih, Meng-Fu ;
Hsu, Yu-Juei .
BIOCHEMICAL JOURNAL, 2014, 464 :221-229
[47]   The association between metabolic syndrome and the anti-aging humoral factor klotho in middle-aged and older adults [J].
Orces, Carlos H. .
DIABETES & METABOLIC SYNDROME-CLINICAL RESEARCH & REVIEWS, 2022, 16 (06)
[48]   Effects of second hand smoke on airway secretion and mucociliary clearance [J].
Liu, Yanyan ;
Di, Y. Peter .
FRONTIERS IN PHYSIOLOGY, 2012, 3
[49]   Aging, Diabetes, and Hypertension Are Associated With Decreased Nasal Mucociliary Clearance [J].
de Oliveira-Maul, Janaina Proenca ;
de Carvalho, Heraclito Barbosa ;
Goto, Danielle Miyuki ;
Maia, Raphaela Mendonca ;
Flo, Claudia ;
Barnabe, Viviane ;
Franco, Denise Reis ;
Benabou, Simon ;
Perracini, Monica Rodrigues ;
Jacob-Filho, Wilson ;
Nascimento Saldiva, Paulo Hilario ;
Lorenzi-Filho, Geraldo ;
Rubin, Bruce K. ;
Nakagawa, Naomi Kondo .
CHEST, 2013, 143 (04) :1091-1097
[50]   Human Skin Aging and the Anti-Aging Properties of Retinol [J].
Quan, Taihao .
BIOMOLECULES, 2023, 13 (11)