Department of Physiology and Membrane Protein Disease Research Group, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Renal Physiol. 2013 Mar 15;304(6):F761-9. doi: 10.1152/ajprenal.00263.2012. Epub 2013 Jan 2.
Kidney stones are a prevalent clinical condition imposing a large economic burden on the healthcare system. Hypercalciuria remains the major risk factor for development of a Ca(2+)-containing stone. The kidney's ability to alter Ca(2+) excretion in response to changes in serum Ca(2+) is in part mediated by the Ca(2+)-sensing receptor (CaSR). Recent studies revealed renal claudin-14 (Cldn14) expression localized to the thick ascending limb (TAL) and its expression to be regulated via the CaSR. We find that Cldn14 expression is increased by high dietary Ca(2+) intake and by elevated serum Ca(2+) levels induced by prolonged 1,25-dihydroxyvitamin D3 administration. Consistent with this, activation of the CaSR in vivo via administration of the calcimimetic cinacalcet hydrochloride led to a 40-fold increase in Cldn14 mRNA. Moreover, overexpression of Cldn14 in two separate cell culture models decreased paracellular Ca(2+) flux by preferentially decreasing cation permeability, thereby increasing transepithelial resistance. These data support the existence of a mechanism whereby activation of the CaSR in the TAL increases Cldn14 expression, which in turn blocks the paracellular reabsorption of Ca(2+). This molecular mechanism likely facilitates renal Ca(2+) losses in response to elevated serum Ca(2+). Moreover, dysregulation of the newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.
肾结石是一种常见的临床病症，给医疗保健系统带来了巨大的经济负担。高钙尿症仍然是形成含钙结石的主要危险因素。肾脏改变钙排泄以适应血清钙变化的能力部分是由钙敏感受体（CaSR）介导的。最近的研究表明，肾脏紧密连接蛋白 14（Cldn14）表达定位于升支粗段（TAL），其表达受 CaSR 调节。我们发现，高钙饮食和延长 1,25-二羟维生素 D3 给药引起的血清钙水平升高均可增加 Cldn14 的表达。与此一致的是，通过给予钙敏感受体激动剂盐酸西那卡塞，体内 CaSR 的激活导致 Cldn14 mRNA 增加了 40 倍。此外，在两种不同的细胞培养模型中过表达 Cldn14 可通过优先降低阳离子通透性来减少细胞旁钙通量，从而增加上皮电阻。这些数据支持这样一种机制，即 TAL 中 CaSR 的激活增加了 Cldn14 的表达，从而阻止了钙的细胞旁重吸收。这种分子机制可能有助于肾脏在血清钙升高时排出钙。此外，新描述的 CaSR-Cldn14 轴的失调可能导致高钙尿症和肾结石的发生。
