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Epithelial Ion Transport in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 5476

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Special Issue Editors

Dr. Michael Gray

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Guest Editor

Biosciences Institute, University Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Interests: epithelial ion transport; ion channels and transporters; cell signaling; pH regulation; cystic fibrosis; pancreatitis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Robert Tarran

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Guest Editor

The Department of Cell Biology & Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Interests: Ca²⁺ signaling; epithelial transport; regulation of ion channels by extracellular proteins; cystic fibrosis

Special Issue Information

Dear Colleagues,

The transport of ions by epithelial cells is essential for a wide range of physiologically important processes, such as acid–base and fluid balance, defense against pathogens, the digestion and absorption of nutrients, efficient sensory transduction, and tissue differentiation as well as repair. Dysfunction in epithelial ion transport underlies many diseases, such as secretory diarrheas, hypertension, COPD, cystic fibrosis, ARDS, pancreatitis, and hydrocephalus, to name just a few. This Special Issue will bring together original research and review articles related to the functional and pathological roles of ion transport in epithelial tissues in health and disease. It will highlight new discoveries, approaches, and technical developments in epithelial research. The main feature of this Special Issue is to highlight emerging new roles played by ion transporters and channels in epithelia, as well as how this information is being harnessed to develop new therapeutic strategies for important human diseases.

Dr. Michael Gray
Prof. Dr. Robert Tarran
Guest Editors

Manuscript Submission Information

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Keywords

epithelial ion transport
epithelial fluid transport
epithelial signaling
epithelial defense
epithelial repair
epithelial differentiation
lungs
gastrointestinal tract
reproductive tract
kidney
liver
pancreas
choroid plexus
salivary glands
diseases of ion transport
chronic inflammatory diseases

Published Papers (5 papers)

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Research

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13 pages, 1603 KiB

Open AccessArticle

by Chien-Te Lee, Hwee-Yeong Ng, Hua-Rong Zhong, Yi Wang, Chih-Han Liu and Yuai-Ting Lee

Int. J. Mol. Sci. 2023, 24(22), 16455; https://doi.org/10.3390/ijms242216455 - 17 Nov 2023

Viewed by 778

Abstract

The kidney plays a crucial role in glucose homeostasis by regulating glucose transport. We aimed to investigate the impact of alterations in glucose transport on glucose metabolism during ageing. Adult male Sprague Dawley rats were divided into five groups: 3-month, 6-month, and 12-month control groups, and 6- and 12-month groups receiving the hydrogen sulfide donor molecule GYY4137. The study found that, as age increased, daily urinary uric acid and protein levels increased in the 12-month group. Blood sugar level and HOMA-IR index increased in the 12-month group, and were partially improved by GYY4137. The kidney tissue showed mild glomerulosclerosis in the 12-month group, which was diminished by GYY4137. Gene expression analysis showed decreased sirtuin and increased p21 expression in the aging groups. Increased SGLT1 and SGLT2 expression was observed in the 12-month group, which was reversed by GYY4137. Both GLUT1 and GLUT2 expression was increased in the 6- and 12-month groups, and reversed by GYY4137 in the 12-month group. The study concluded that aging was associated with increased blood sugar levels and the HOMA-IR index, and the abundance of renal glucose transporters increased as aging progressed. GYY4137 effectively reversed aging-related alterations in glucose homeostasis and renal epithelial transporters. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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15 pages, 2824 KiB

Open AccessArticle

Vaping-Induced Proteolysis Causes Airway Surface Dehydration

by Arunava Ghosh, Raymond D. Coakley, Neil E. Alexis and Robert Tarran

Int. J. Mol. Sci. 2023, 24(20), 15348; https://doi.org/10.3390/ijms242015348 - 19 Oct 2023

Viewed by 902

Abstract

Proteases such as neutrophil elastase cleave and activate the epithelial sodium channel (ENaC), causing airway dehydration. Our current study explores the impact of increased protease levels in vapers’ airways on ENaC activity and airway dehydration. Human bronchial epithelial cultures (HBECs) were exposed to bronchoalveolar lavage fluid (BALF) from non-smokers, smokers and vapers. Airway surface liquid (ASL) height was measured by confocal microscopy as a marker of hydration. ENaC cleavage was measured by Western blotting. Human peripheral blood neutrophils were treated with a menthol-flavored e-liquid (Juul), and the resulting secretions were added to HBECs. BALF from smokers and vapers significantly and equally increased ENaC activity and decreased ASL height. The ASL height decrease was attenuated by protease inhibitors. Non-smokers’ BALF had no effect on ENaC or ASL height. BALF from smokers and vapers, but not non-smokers, induced ENaC cleavage. E-liquid-treated neutrophil secretions cleaved ENaC and decreased ASL height. Our study demonstrated that elevated protease levels in vapers’ airways have functional significance since they can activate ENaC, resulting in airway dehydration. Lung dehydration contributes to diseases like cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Thus, our data predict that vaping, like smoking, will cause airway surface dehydration that likely leads to lung disease. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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14 pages, 3915 KiB

Open AccessArticle

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes

by Juliet W. Lefferts, Marlou C. Bierlaagh, Suzanne Kroes, Natascha D. A. Nieuwenhuijze, Heleen N. Sonneveld van Kooten, Paul J. Niemöller, Tibo F. Verburg, Hettie M. Janssens, Danya Muilwijk, Sam F. B. van Beuningen, Cornelis K. van der Ent and Jeffrey M. Beekman

Int. J. Mol. Sci. 2023, 24(19), 14539; https://doi.org/10.3390/ijms241914539 - 26 Sep 2023

Cited by 4 | Viewed by 1502

Abstract

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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21 pages, 11662 KiB

Open AccessArticle

The Anion Channel TMEM16a/Ano1 Modulates CFTR Activity, but Does Not Function as an Apical Anion Channel in Colonic Epithelium from Cystic Fibrosis Patients and Healthy Individuals

by Azam Salari, Renjie Xiu, Mahdi Amiri, Sophia Theres Pallenberg, Rainer Schreiber, Anna-Maria Dittrich, Burkhard Tümmler, Karl Kunzelmann and Ursula Seidler

Int. J. Mol. Sci. 2023, 24(18), 14214; https://doi.org/10.3390/ijms241814214 - 18 Sep 2023

Cited by 2 | Viewed by 932

Abstract

Studies in human colonic cell lines and murine intestine suggest the presence of a Ca²⁺-activated anion channel, presumably TMEM16a. Is there a potential for fluid secretion in patients with severe cystic fibrosis transmembrane conductance regulator (CFTR) mutations by activating this alternative pathway? Two-dimensional nondifferentiated colonoid–myofibroblast cocultures resembling transit amplifying/progenitor (TA/PE) cells, as well as differentiated monolayer (DM) cultures resembling near-surface cells, were established from both healthy controls (HLs) and patients with severe functional defects in the CFTR gene (PwCF). F508del mutant and CFTR knockout (null) mice ileal and colonic mucosa was also studied. HL TA/PE monolayers displayed a robust short-circuit current response (ΔI_eq) to UTP (100 µM), forskolin (Fsk, 10 µM) and carbachol (CCH, 100 µM), while ΔI_eq was much smaller in differentiated monolayers. The selective TMEM16a inhibitor Ani9 (up to 30 µM) did not alter the response to luminal UTP, significantly decreased Fsk-induced ΔI_eq, and significantly increased CCH-induced ΔI_eq in HL TA/PE colonoid monolayers. The PwCF TA/PE and the PwCF differentiated monolayers displayed negligible agonist-induced ΔI_eq, without a significant effect of Ani9. When TMEM16a was localized in intracellular structures, a staining in the apical membrane was not detected. TMEM16a is highly expressed in human colonoid monolayers resembling transit amplifying cells of the colonic cryptal neck zone, from both HL and PwCF. While it may play a role in modulating agonist-induced CFTR-mediated anion currents, it is not localized in the apical membrane, and it has no function as an apical anion channel in cystic fibrosis (CF) and healthy human colonic epithelium. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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Review

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19 pages, 2355 KiB

Open AccessReview

Intercellular Communication in Airway Epithelial Cell Regeneration: Potential Roles of Connexins and Pannexins

by Mehdi Badaoui and Marc Chanson

Int. J. Mol. Sci. 2023, 24(22), 16160; https://doi.org/10.3390/ijms242216160 - 10 Nov 2023

Viewed by 798

Abstract

Connexins and pannexins are transmembrane proteins that can form direct (gap junctions) or indirect (connexons, pannexons) intercellular communication channels. By propagating ions, metabolites, sugars, nucleotides, miRNAs, and/or second messengers, they participate in a variety of physiological functions, such as tissue homeostasis and host defense. There is solid evidence supporting a role for intercellular signaling in various pulmonary inflammatory diseases where alteration of connexin/pannexin channel functional expression occurs, thus leading to abnormal intercellular communication pathways and contributing to pathophysiological aspects, such as innate immune defense and remodeling. The integrity of the airway epithelium, which is the first line of defense against invading microbes, is established and maintained by a repair mechanism that involves processes such as proliferation, migration, and differentiation. Here, we briefly summarize current knowledge on the contribution of connexins and pannexins to necessary processes of tissue repair and speculate on their possible involvement in the shaping of the airway epithelium integrity. Full article

(This article belongs to the Special Issue Epithelial Ion Transport in Health and Disease)

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