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  Claudin-10a deficiency shifts proximal tubular Cl-permeability to cation selectivity via claudin-2 redistribution

Breiderhoff, T., Himmerkus, N., Meoli, L., Fromm, A., Sewerin, S., Kriuchkova, N., et al. (2022). Claudin-10a deficiency shifts proximal tubular Cl-permeability to cation selectivity via claudin-2 redistribution. Journal of the American Society of Nephrology. doi:10.1681/ASN.2021030286.

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Breiderhoff, Tilman1, Author
Himmerkus, Nina2, Author
Meoli, Luca3, Author
Fromm, Anja3, Author
Sewerin, Sebastian4, Author
Kriuchkova, Natalia5, Author
Nagel, Oliver3, Author
Ladilov, Yury3, Author
Krug, Susanne M.3, Author
Quintanova, Catarina2, Author
Stumpp, Meike6, Author
Garbe-Schönberg, Dieter7, Author
Westernströer, Ulrike7, Author
Merkel, Cosima2, Author
Brinkhus, Merle Annette2, Author
Altmüller, Janine8, 9, 10, Author
Schweiger, Michal R.8, 11, 12, Author
Müller, Dominik1, Author
Mutig, Kerim13, 14, Author
Morawski, Markus15, 16, Author              
Halbritter, Jan4, 17, AuthorMilatz, Susanne2, AuthorBleich, Markus2, AuthorGünzel, Dorothee3, Author more..
Affiliations:
1Division of Gastroenterology, Nephrology and Metabolic Diseases, Department of Pediatrics, Charité University Medicine Berlin, Germany, ou_persistent22              
2Institute of Physiology, Christian Albrecht University Kiel, Germany, ou_persistent22              
3Clinical Physiology / Nutritional Medicine, Department of Gastroenterology, Rheumatology, and Infectious Diseases, Charité University Medicine Berlin, Germany, ou_persistent22              
4Clinic for Endocrinology and Nephrology, University Hospital Leipzig, Germany, ou_persistent22              
5Institute for Functional Anatomy, Charité University Medicine Berlin, Germany, ou_persistent22              
6Department of Comparative Immunobiology, Zoological Institute, Christian Albrecht University Kiel, Germany, ou_persistent22              
7Institute of Geosciences, Christian Albrecht University Kiel, Germany, ou_persistent22              
8Cologne Center for Genomics (CCG), University of Cologne, Germany, ou_persistent22              
9Berlin Institute of Health (BIH), Germany, ou_persistent22              
10Max Delbrück Center for Molecular Medicine, Berlin, Germany, ou_persistent22              
11Institute for Translational Epigenetics, University Hospital Cologne, Germany, ou_persistent22              
12Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Germany, ou_persistent22              
13Institute of Vegetative Physiology, Charité University Medicine Berlin, Germany, ou_persistent22              
14Department of Pharmacology, Ministry of Healthcare of the Russian Federation, Moscow, Russia, ou_persistent22              
15Paul Flechsig Institute for Brain Research, University of Leipzig, Germany, ou_persistent22              
16Department Neurophysics (Weiskopf), MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_2205649              
17Department of Nephrology and Medical Intensive Care, Charité University Medicine Berlin, Germany, ou_persistent22              

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Free keywords: Calcium; Ion transport; Pathophysiology of kidney disease and progression
 Abstract: Background The tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear. Methods To investigate the physiologic role of claudin-10a, we generated claudin-10a–deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry. Results Mice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl- over HCO3- preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport. Conclusions Claudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability.

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Language(s): eng - English
 Dates: 2022-01-14
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1681/ASN.2021030286
Other: online ahead of print
PMID: 35031570
 Degree: -

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Title: Journal of the American Society of Nephrology
Source Genre: Journal
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Publ. Info: Baltimore, MD : Williams & Wilkins
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 1046-6673
CoNE: https://pure.mpg.de/cone/journals/resource/991042727101258_1