Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease
Joshua N. Curry, … , Koichi Matsuda, Alan S.L. Yu
Joshua N. Curry, … , Koichi Matsuda, Alan S.L. Yu
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1948-1960. https://doi.org/10.1172/JCI127750.
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Research Article Cell biology Nephrology

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

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 key regulator of calcium excretion and a potential target for therapies to prevent kidney stones.

Authors

Joshua N. Curry, Matthew Saurette, Masomeh Askari, Lei Pei, Michael B. Filla, Megan R. Beggs, Peter S.N. Rowe, Timothy Fields, Andre J. Sommer, Chizu Tanikawa, Yoichiro Kamatani, Andrew P. Evan, Mehdi Totonchi, R. Todd Alexander, Koichi Matsuda, Alan S.L. Yu

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Figure 6

Calcium deposits in the papilla of Cldn2–/y mice.

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Calcium deposits in the papilla of Cldn2–/y mice. (A–C) Representative k...
(A–C) Representative kidney sections from 6-month-old Cldn2–/y mice were stained and visualized with the following methods: (A) Von Kossa. (B) Alizarin red S (ARS), pH 4.2, bright field. (C) ARS, pH 4.2, polarized light. Scale bars: 100 μm. (D) Micro-FTIR analysis shows that deposits are composed of primarily hydroxyapatite. (E) TEM reveals large-diameter aggregates of matrix and mineral with laminated deposits characteristic of hydroxyapatite. Scale bar: 2 μm. (F and G) Representative 3D reconstructions of micro-CT analysis of kidneys from WT (blue outline) and Cldn2–/y (red outline) (F) and quantitation of the mineral volume in reconstruction analysis (n = 2–5 per group) (G). Data were normalized for each time point and log-transformed before plotting for analysis. Bars are mean ± SEM. At each time point, differences between WT and Cldn2–/y were analyzed by unpaired t test and corrected for multiple comparisons using the Bonferroni-Dunn method; *P < 0.05, **P < 0.01.