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- Title
Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease.
- Authors
Curry, Joshua N.; Saurette, Matthew; Askari, Masomeh; Pei, Lei; Filla, Michael B.; Beggs, Megan R.; Rowe, Peter S. N.; Fields, Timothy; Sommer, Andre J.; Chizu Tanikawa; Yoichiro Kamatani; Evan, Andrew P.; Totonchi, Mehdi; Alexander, R. Todd; Koichi Matsuda; Yu, Alan S. L.; Rowe, Peter Sn; Tanikawa, Chizu; Kamatani, Yoichiro; Matsuda, Koichi
- 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.
- Subjects
ANIMAL experimentation; CALCIUM; COMPARATIVE studies; GENES; GENETICS; HYPERCALCIUREA; KIDNEY tubules; KIDNEY stones; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 4, p1948
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI127750