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Functional Role of Basolateral ClC-2 Channels in the Regulation of Duodenal Anion Secretion in Mice

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Abstract

Background

Although ClC-2 channels are important in colonic Cl− secretion, it is unclear about their roles in small intestinal anion secretion. Therefore, we sought to examine whether ClC-2 channels play important roles in anion secretion, particularly duodenal bicarbonate secretion (DBS).

Methods

Duodenal mucosae from mice were stripped of seromuscular layers and mounted in Ussing chambers. Both duodenal short-circuit current (Isc) and HCO3− secretion in vitro were simultaneously recorded. DBS in vivo was measured by a CO2-sensitive electrode.

Results

Lubiprostone, a selective ClC-2 activator, concentration-dependently increased both duodenal Isc and DBS only when applied basolaterally, but not when applied apically. Removal of extracellular Cl− abolished lubiprostone-induced duodenal Isc, but did not alter HCO3− secretion even in the presence of DIDS, a Cl−/HCO3− exchanger inhibitor. However, further addition of glibenclamide, a CFTR channel blocker, abolished lubiprostone-evoked HCO3− secretion. Moreover, lubiprostone-induced HCO3− secretion was impaired in CFTR−/− mice compared to wild-type littermates. Luminal perfusion of duodenal lumen with lubiprostone did not alter basal DBS in vivo, but lubiprostone (i.p.) was able to induce DBS, which was also significantly inhibited by Cd2+, a ClC-2 channel blocker. [Ca2+]cyt level, Ca2+-activated K+ channel- and cAMP-mediated duodenal Isc, and HCO3− secretion were unchanged by lubiprostone.

Conclusions

We have provided the first evidence for the novel functional role of basolateral ClC-2 channels in the regulation of duodenal anion secretion.

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Abbreviations

CFTR:

Cystic fibrosis transmembrane conductance regulator

DBS:

Duodenal bicarbonate secretion

AE:

Anion exchangers

NBC:

Na+/HCO3− cotransporters

TER:

Transepithelial resistance

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Acknowledgments

These studies were supported by research grants from the National Key Research and Development Program of China (No. 2016YFC1302200 to HD) and the National Natural Science Foundation of China (Nos. 81570477 and 81873544 to HD).

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Author notes

  1. Chao Du and Jingjing Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China

    Chao Du, Jingjing Liu, Hanxing Wan, Hui Dong & Xiaoyan Zhao

  2. Department of Medicine, School of Medicine, University of California, San Diego, CA, 92093, USA

    Hui Dong

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  1. Chao Du
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Contributions

HD designed and supervised the project, wrote and finalized the manuscript. CD and JL conducted most experiments and data analysis. HXW conducted some experiments. XZ finalized the manuscript. All authors reviewed the manuscript.

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Correspondence to Hui Dong or Xiaoyan Zhao.

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Du, C., Liu, J., Wan, H. et al. Functional Role of Basolateral ClC-2 Channels in the Regulation of Duodenal Anion Secretion in Mice. Dig Dis Sci 64, 2527–2537 (2019). https://doi.org/10.1007/s10620-019-05578-7

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