Breiderhoff, Tilman ORCID: 0000-0002-1676-7498, Himmerkus, Nina ORCID: 0000-0002-2910-6728, Meoli, Luca ORCID: 0000-0002-9853-2624, Fromm, Anja, Sewerin, Sebastian ORCID: 0000-0002-9094-9636, Kriuchkova, Natalia ORCID: 0000-0002-9795-2440, Nagel, Oliver ORCID: 0000-0003-1434-726X, Ladilov, Yury ORCID: 0000-0002-9836-8801, Krug, Susanne M., Quintanova, Catarina ORCID: 0000-0001-6617-2006, Stumpp, Meike ORCID: 0000-0001-7765-2996, Garbe-Schoenberg, Dieter, Westernstroeer, Ulrike, Merkel, Cosima, Brinkhus, Merle Annette, Altmuller, Janine ORCID: 0000-0003-4372-1521, Schweiger, Michal R., Muller, Dominik, Mutig, Kerim, Morawski, Markus, Halbritter, Jan ORCID: 0000-0002-1377-9880, Milatz, Susanne ORCID: 0000-0001-9893-0473, Bleich, Markus ORCID: 0000-0002-1745-2295 and Guenzel, Dorothee (2022). Claudin-10a Deficiency Shifts Proximal Tubular Cl- Permeability to Cation Selectivity via Claudin-2 Redistribution. J. Am. Soc. Nephrol., 33 (4). S. 699 - 718. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Breiderhoff, TilmanUNSPECIFIEDorcid.org/0000-0002-1676-7498UNSPECIFIED
Himmerkus, NinaUNSPECIFIEDorcid.org/0000-0002-2910-6728UNSPECIFIED
Meoli, LucaUNSPECIFIEDorcid.org/0000-0002-9853-2624UNSPECIFIED
Fromm, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sewerin, SebastianUNSPECIFIEDorcid.org/0000-0002-9094-9636UNSPECIFIED
Kriuchkova, NataliaUNSPECIFIEDorcid.org/0000-0002-9795-2440UNSPECIFIED
Nagel, OliverUNSPECIFIEDorcid.org/0000-0003-1434-726XUNSPECIFIED
Ladilov, YuryUNSPECIFIEDorcid.org/0000-0002-9836-8801UNSPECIFIED
Krug, Susanne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quintanova, CatarinaUNSPECIFIEDorcid.org/0000-0001-6617-2006UNSPECIFIED
Stumpp, MeikeUNSPECIFIEDorcid.org/0000-0001-7765-2996UNSPECIFIED
Garbe-Schoenberg, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westernstroeer, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkel, CosimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkhus, Merle AnnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDorcid.org/0000-0003-4372-1521UNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mutig, KerimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morawski, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbritter, JanUNSPECIFIEDorcid.org/0000-0002-1377-9880UNSPECIFIED
Milatz, SusanneUNSPECIFIEDorcid.org/0000-0001-9893-0473UNSPECIFIED
Bleich, MarkusUNSPECIFIEDorcid.org/0000-0002-1745-2295UNSPECIFIED
Guenzel, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-691877
DOI: 10.1681/ASN.2021030286
Journal or Publication Title: J. Am. Soc. Nephrol.
Volume: 33
Number: 4
Page Range: S. 699 - 718
Date: 2022
Publisher: AMER SOC NEPHROLOGY
Place of Publication: WASHINGTON
ISSN: 1533-3450
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TIGHT JUNCTION PROTEINS; THICK ASCENDING LIMBS; EXTRACELLULAR-MATRIX; TRANSPORT; EXPRESSION; CLDN10; MICE; REABSORPTION; ABSORPTION; MECHANISMSMultiple languages
Urology & NephrologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69187

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