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ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/JCI197807

Kidney-specific claudin-2 deficiency leads to medullary nephrocalcinosis in mice

Christine V. Behm,1 Duuamene Nyimanu,1 Ony Araujo Galdino,2 Sadhana Kanoo,2 Young Chul Kim,2 Natalia Lopez,2 Helen Goodluck,2 Peter S. Rowe,3 Andrew P. Evan,4 André J. Sommer,4 Matthew N. Barr,5 Tracy Punshon,5 Volker Vallon,2 Brian P. Jackson,5 James C. Williams Jr.,4 and Alan S.L. Yu3

1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

Find articles by Jackson, B. in: PubMed | Google Scholar

1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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1Division of Nephrology and Hypertension, Department of Internal Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

2Division of Nephrology and Hypertension, Department of Medicine, UCSD, La Jolla, United States of America

3Division of Nephrology and Hypertension, Department of Medicine, Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, United States of America

4Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, United States of America

5Biomedical National Elemental Imaging Resource, Department of Earth Science, Dartmouth College, Hanover, United States of America

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Published October 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI197807.
Copyright © 2025, Behm et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 9, 2025 - Version history
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Abstract

Deposits of hydroxyapatite called Randall's plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule-specific claudin-2 conditional knockout mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall's plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation-inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice, that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the “vas washdown” hypothesis for Randall's plaque formation, and identify the corticomedullary calcium gradient as a target for therapies to prevent kidney stone disease.

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  • Version 1 (October 9, 2025): In-Press Preview
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