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Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease.
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2020-03-09 , DOI: 10.1172/jci127750
Joshua N Curry 1, 2 , Matthew Saurette 3, 4 , Masomeh Askari 5 , Lei Pei 6 , Michael B Filla 2, 6 , Megan R Beggs 3, 4 , Peter Sn Rowe 2, 6 , Timothy Fields 7 , Andre J Sommer 8 , Chizu Tanikawa 9 , Yoichiro Kamatani 10 , Andrew P Evan 11 , Mehdi Totonchi 5, 12 , R Todd Alexander 4, 13 , Koichi Matsuda 9, 14 , Alan Sl Yu 1, 2, 6
Affiliation  

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.

中文翻译:


Claudin-2 缺乏症与小鼠高钙尿症和人类肾结石疾病有关。



肾结石病的主要危险因素是特发性高钙尿症。最近的证据表明肾近曲小管中钙重吸收缺陷的作用。我们假设 Claudin-2(一种细胞旁阳离子通道蛋白)介导近端小管钙重吸收。我们发现claudin-2缺失小鼠患有高钙尿症,这是由于肾小管钙转运的主要缺陷和乳头状肾钙质沉着症(类似于肾结石形成者中的肾小管内栓子)造成的。我们的研究结果表明,钙重吸收的近端小管缺陷容易导致乳头状钙化,这为输精管冲洗假说提供了支持。还发现 Claudin-2 缺失小鼠的肠道钙净吸收增加,但结肠中的细胞旁钙渗透性降低,表明这是由于肠道钙分泌减少所致。在两项大型人群研究中,claudin-2 基因的常见遗传变异与 claudin-2 组织表达减少和肾结石风险增加相关。最后,我们描述了一个家族,其中具有罕见的claudin-2错义变异的男性患有明显的高钙尿症和肾结石疾病。我们的研究结果表明,claudin-2 是钙排泄的关键调节剂,也是预防肾结石治疗的潜在靶标。
更新日期:2020-04-03
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