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

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

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1948-1960
Number of pages13
JournalJournal of Clinical Investigation
Volume130
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Curry, J. N., Saurette, M., Askari, M., Pei, L., Filla, M. B., Beggs, M. R., Rowe, P. S. N., Fields, T., Sommer, A. J., Tanikawa, C., Kamatani, Y., Evan, A. P., Totonchi, M., Todd Alexander, R., Matsuda, K., & Yu, A. S. L. (2020). Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease. Journal of Clinical Investigation, 130(4), 1948-1960. https://doi.org/10.1172/JCI127750