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

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

doi:10.1172/jci127750

Cited by 70 publications

(103 citation statements)

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“…However, when luminal calcium levels are lower than plasma, having more intestinal calcium permeability may be counterproductive, and enhance calcium secretion and thus loss in faeces (Curry et al . 2020). Clearly there are further questions with respect to how intestinal calcium absorption is increased in response to calcitriol.…”

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confidence: 99%

Increased intestinal phosphate absorption, an often‐overlooked effect of vitamin D

Alexander

2020

The Journal of Physiology

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confidence: 99%

Increased intestinal phosphate absorption, an often‐overlooked effect of vitamin D

Alexander

2020

The Journal of Physiology

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“…Therefore, based on these earlier findings, the upregulation of claudin 2 mRNA and protein levels demonstrated in the current study is the most likely contributor to the increase in duodenal calcium absorption seen in response to iron deficiency. However, it should be noted that while a recent study by Curry et al established that claudin 2 knockout mice have a decrease in passive calcium permeability, this adaptation is confined to the colon, where under normal physiological conditions the protein is likely to mediate calcium secretion 51 . Whether differences in the regional profile of claudin 2 in rats versus mice, combined with the local environment in which the protein is maximally expressed, impact the absorptive or secretory function of this protein requires further investigation.…”

Section: Discussionmentioning

confidence: 98%

Diet‐induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption

et al. 2021

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Aims Recent reports suggest that iron deficiency impacts both intestinal calcium and phosphate absorption, although the exact transport pathways and intestinal segment responsible have not been determined. Therefore, we aimed to systematically investigate the impact of iron deficiency on the cellular mechanisms of transcellular and paracellular calcium and phosphate transport in different regions of the rat small intestine. Methods Adult, male Sprague‐Dawley rats were maintained on a control or iron‐deficient diet for 2 weeks and changes in intestinal calcium and phosphate uptake were determined using the in situ intestinal loop technique. The circulating levels of the hormonal regulators of calcium and phosphate were determined by ELISA, while the expression of transcellular calcium and phosphate transporters, and intestinal claudins were determined using qPCR and western blotting. Results Diet‐induced iron deficiency significantly increased calcium absorption in the duodenum but had no impact in the jejunum and ileum. In contrast, phosphate absorption was significantly inhibited in the duodenum and to a lesser extent the jejunum, but remained unchanged in the ileum. The changes in duodenal calcium and phosphate absorption in the iron‐deficient animals were associated with increased claudin 2 and 3 mRNA and protein levels, while levels of parathyroid hormone, fibroblast growth factor‐23 and 1,25‐dihydroxy vitamin D3 were unchanged. Conclusion We propose that iron deficiency alters calcium and phosphate transport in the duodenum. This occurs via changes to the paracellular pathway, whereby upregulation of claudin 2 increases calcium absorption and upregulation of claudin 3 inhibits phosphate absorption.

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“…Patients with mutations in the CLDN16 or CLDN19 genes, which are characterized by excessive renal magnesium and calcium excretion, are diagnosed with a syndrome of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) [ 70 ]. Recent novel studies revealed CLDN2 is the mediator of calcium reabsorption in the PT and plays a critical role in idiopathic hypercalciuria and nephrolithiasis [ 71 ]. CLDN2-knockout mice were found to have hypercalciuria attributable to both a renal leak of calcium and increased net intestinal calcium absorption.…”

Section: Ca 2+ Signaling In Nephrolithiasismentioning

confidence: 99%

Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification

Liu

Cheng

Tsai

et al. 2021

IJMS

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Calcium (Ca2+) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca2+ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca2+ regulation. CaSR is important for renal Ca2+, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca2+ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca2+ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.

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

Cited by 70 publications

References 71 publications

Increased intestinal phosphate absorption, an often‐overlooked effect of vitamin D

Increased intestinal phosphate absorption, an often‐overlooked effect of vitamin D

Diet‐induced iron deficiency in rats impacts small intestinal calcium and phosphate absorption

Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification

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