Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease.

The Journal of Clinical Investigation
Joshua N CurryAlan S L Yu

Abstract

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2-null mice have hypercalciuria due to a primary defect in renal tubule calcium transport and papillary nephrocalcinosis that resembles the intratubular plugs in kidney stone formers. Our findings suggest that a proximal tubule defect in calcium reabsorption predisposes to papillary calcification, providing support for the vas washdown hypothesis. Claudin-2-null mice were also found to have increased net intestinal calcium absorption, but reduced paracellular calcium permeability in the colon, suggesting that this was due to reduced intestinal calcium secretion. Common genetic variants in the claudin-2 gene were associated with decreased tissue expression of claudin-2 and increased risk of kidney stones in 2 large population-based studies. Finally, we describe a family in which males with a rare missense variant in claudin-2 have marked hypercalciuria and kidney stone disease. Our findings indicate that claudin-2 is a...Continue Reading

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Citations

Apr 11, 2020·Nature Reviews. Urology·Annette Fenner
Mar 27, 2020·Nature Reviews. Nephrology·Susan J Allison
Dec 10, 2020·The Journal of Physiology·R Todd Alexander
Feb 25, 2021·Journal of Experimental & Clinical Cancer Research : CR·Balawant KumarAmar B Singh
Apr 3, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Mallory L Downie, R Todd Alexander
Apr 4, 2021·International Journal of Molecular Sciences·Chan-Jung LiuHo-Shiang Huang
May 26, 2021·Nature Reviews. Urology·Mayandi SivaguruBruce W Fouke
Jul 13, 2020·Kidney International·Valentine Gillion, Olivier Devuyst
Aug 7, 2021·Frontiers in Oncology·Jian Li
May 29, 2021·Journal of the American Society of Nephrology : JASN·David H EllisonJames A McCormick

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Methods Mentioned

BETA
infrared spectroscopy
electrophoresis
ELISA
reverse transcription PCR
PCR
dissecting
genotyping
urine collections

Software Mentioned

METAL
minimac
Spectrum Image
MaCH
FastQTL
ImageJ
GraphPad Prism

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