Chattopadhyay N, Baum M, Bai M, Riccardi D, Hebert S C, Harris H W, Brown E M
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Physiol. 1996 Sep;271(3 Pt 2):F736-43. doi: 10.1152/ajprenal.1996.271.3.F736.
We recently cloned extracellular Ca(2+)-sensing receptors (CaRs) from bovine parathyroid and rat kidney that play key roles in Ca2+ homeostasis. Inactivating mutations of the CaR in the inherited human disorder, familial hypocalciuric hypercalcemia, cause reduced responsiveness of the parathyroid to extracellular Ca2+ (Cao2+), as well as abnormally avid renal tubular reabsorption of both Ca2+ and Mg2+ in the distal tubule, suggesting an important role for the CaR in regulating parathyroid hormone (PTH) secretion and renal handling of divalent cations. High Cao2+ also inhibits vasopressinstimulated adenosine 3',5'-cyclic monophosphate accumulation in the medullary thick ascending limb (MTAL) and water reabsorption in the collecting duct (CD) and modulates various other aspects of renal function. The relevance of the CaR to these processes, however, is uncertain. Reduced responsiveness of vasopressin-and PTH-mediated actions on the kidney have been described in the newborn that could potentially reflect effects of the CaR on these aspects of renal function. To define further the role of the CaR in regulating renal function, including the above-mentioned changes during the perinatal period, therefore, we have studied its ontogeny in rat kidney. Northern and Western blot analyses, as well as immunohistochemistry with CaR-specific probes, demonstrate that there is little prenatal expression of the extracellular Ca(2+)-sensing receptor, except in large tubules and branching ureteric buds of developing nephrons. Postnatally, CaR mRNA and protein increase markedly during the 1st wk, related principally to expression of the receptor in the developing TAL and, to a lesser extent, in the CD. The level of expression of the receptor remains nearly constant after postnatal day 14. These results demonstrate that the perinatal increases in expression of CaR mRNA and protein parallel its tissue-specific renal expression. Furthermore, it is possible that some of the previously described changes in renal handling of divalent cations and water in the perinatal and immediate postnatal period are related, in part, to the increasing levels of expression of the CaR and resultant inhibitory effects on the actions of PTH and antidiuretic hormone on the developing nephron.
我们最近从牛甲状旁腺和大鼠肾脏中克隆出细胞外钙（Ca²⁺）感受受体（CaRs），它们在钙稳态中起关键作用。遗传性人类疾病家族性低钙血症性高钙血症中CaR的失活突变导致甲状旁腺对细胞外钙（Ca₂⁺o）的反应性降低，以及远曲小管对钙和镁的异常强烈的肾小管重吸收，这表明CaR在调节甲状旁腺激素（PTH）分泌和肾脏对二价阳离子的处理中起重要作用。高Ca₂⁺o还抑制血管加压素刺激的髓质厚升支（MTAL）中3',5'-环磷酸腺苷的积累以及集合管（CD）中的水重吸收，并调节肾功能的其他各个方面。然而，CaR与这些过程的相关性尚不确定。在新生儿中已描述了血管加压素和PTH介导的对肾脏作用的反应性降低，这可能潜在地反映了CaR对肾功能这些方面的影响。因此，为了进一步确定CaR在调节肾功能中的作用，包括围产期上述变化，我们研究了其在大鼠肾脏中的个体发生。Northern和Western印迹分析以及用CaR特异性探针进行的免疫组织化学表明，除了在发育中的肾单位的大肾小管和分支输尿管芽中外，细胞外钙（Ca²⁺）感受受体在产前几乎没有表达。出生后，CaR mRNA和蛋白质在第1周内显著增加主要与该受体在发育中的TAL中的表达有关，在较小程度上与在CD中的表达有关。出生后第14天之后，该受体的表达水平几乎保持恒定。这些结果表明，围产期CaR mRNA和蛋白质表达的增加与其在肾脏中的组织特异性表达平行。此外，围产期和出生后即刻肾脏对二价阳离子和水的处理中一些先前描述的变化可能部分与CaR表达水平的增加以及对PTH和抗利尿激素对发育中的肾单位作用的抑制作用有关。
