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| Item Type: | Article |
|---|---|
| Title: | Claudin-10a deficiency shifts proximal tubular Cl(-) permeability to cation selectivity via claudin-2 redistribution |
| Creators Name: | Breiderhoff, T., Himmerkus, N., Meoli, L., Fromm, A., Sewerin, S., Kriuchkova, N., Nagel, O., Ladilov, Y., Krug, S., Quintanova, C., Stumpp, M., Garbe-Schönberg, D., Westernströer, U., Merkel, C., Brinkhus, M., Altmüller, J., Schweiger, M., Mueller, D., Mutig, K., Morawski, M., Halbritter, J., Milatz, S., Bleich, M. and Günzel, D. |
| 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 physiological 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. Upon 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 consequence, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison of other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, as well as 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. CONCLLUSIONS: Claudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyperreabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability. |
| Keywords: | Cations, Claudin-2, Claudins, Proximal Kidney Tubules, Permeability, Tight Junctions / Physiology, Animals, Mice |
| Source: | Journal of the American Society of Nephrology |
| ISSN: | 1046-6673 |
| Publisher: | American Society of Nephrology |
| Volume: | 33 |
| Number: | 4 |
| Page Range: | 699-717 |
| Date: | April 2022 |
| Additional Information: | Copyright © 2022 by the American Society of Nephrology |
| Official Publication: | https://doi.org/10.1681/ASN.2021030286 |
| PubMed: | View item in PubMed |
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