Himmerkus Nina, Quintanova Catarina, Bhullar Harneet, van Megen Wouter H, Deluque Amanda Lima, Skjødt Karsten, Bogdanovic Milos, Bleich Markus, Alexander R Todd, Dimke Henrik
Institute of Physiology, Christian-Albrechts-University, Kiel, Germany.
Membrane Protein Disease Research Group, The University of Alberta, Edmonton, Alberta, Canada.
J Am Soc Nephrol. 2025 Jun 1;36(6):1028-1039. doi: 10.1681/ASN.0000000612. Epub 2025 Jan 22.
The thick ascending limb (TAL) calcium-sensing receptor (CaSR) was critical for controlling calcium excretion in response to hypercalcemia but did not alter urinary magnesium excretion. CaSR activation increased urinary calcium excretion by strongly reducing calcium permeability in the TAL. Activation of the CaSR did not affect the driving force generated by transcellular NaCl transport across the TAL.
The parathyroid calcium-sensing receptor (CaSR) controls the release of parathyroid hormone in response to changes in serum calcium levels. Activation of the renal CaSR increases urinary calcium excretion and is particularly important when CaSR-dependent reductions in parathyroid hormone fail to lower serum calcium. However, the role of the renal CaSR in protecting against hypercalcemia and the direct effects of chronic CaSR activation on tubular calcium handling remain to be fully elucidated.
Experimental hypercalcemia was induced using a vitamin D analog (dihydrotachysterol) in mice with -Cre–dependent deletion of the (-) in the kidney, with Cre-negative littermates serving as controls (here denoted wild-types [WT]). Urinary and fecal electrolyte determinations, dual-energy x-ray absorptiometry, molecular and biochemical evaluation, and tubule microperfusion were performed in both sexes.
-Cre–driven deletion strongly reduced CaSR abundance in the thick ascending limb (TAL). At baseline, no marked differences were detected in electrolyte handling and tubular permeability characteristics across the TAL. Three days of dihydrotachysterol administration induced hypercalcemia in both WT and - mice. However, although WT mice developed hypercalciuria, this response was absent in - mice. Urinary excretion of magnesium and other electrolytes did not differ between hypercalcemic WT and - mice. Intestinal electrolyte absorption was comparable between the two groups. Microperfusion of isolated cortical TALs revealed no baseline differences in transepithelial voltage, resistance, or ion permeabilities. After hypercalcemia, transepithelial resistance increased and calcium permeability markedly decreased in WT mice, but not in mice, with only minor alterations in magnesium permeability and no changes in transepithelial voltage.
In hypercalcemic mice, the absence of the CaSR in TAL prevented the increase in urinary calcium excretion. The CaSR specifically regulated the paracellular permeability of the TAL, especially for calcium.
厚壁升支粗段（TAL）钙敏感受体（CaSR）对于控制高钙血症时的钙排泄至关重要，但不改变尿镁排泄。CaSR激活通过强烈降低TAL中的钙通透性来增加尿钙排泄。CaSR的激活不影响跨TAL的细胞间NaCl转运所产生的驱动力。
甲状旁腺钙敏感受体（CaSR）根据血清钙水平的变化控制甲状旁腺激素的释放。肾CaSR的激活增加尿钙排泄，当依赖CaSR的甲状旁腺激素减少未能降低血清钙时，这一点尤为重要。然而，肾CaSR在预防高钙血症中的作用以及慢性CaSR激活对肾小管钙处理的直接影响仍有待充分阐明。
使用维生素D类似物（二氢速甾醇）在肾中依赖-Cre缺失（-）的小鼠中诱导实验性高钙血症，Cre阴性同窝小鼠作为对照（此处称为野生型[WT]）。对雌雄小鼠均进行了尿和粪便电解质测定、双能X线吸收法、分子和生化评估以及肾小管微灌注。
-Cre驱动的缺失强烈降低了厚壁升支粗段（TAL）中CaSR的丰度。在基线时，跨TAL的电解质处理和肾小管通透性特征未检测到明显差异。给予二氢速甾醇三天后，WT小鼠和-小鼠均出现高钙血症。然而，虽然WT小鼠出现高钙尿，但-小鼠没有这种反应。高钙血症的WT小鼠和-小鼠之间尿镁和其他电解质的排泄没有差异。两组之间肠道电解质吸收相当。分离的皮质TAL的微灌注显示跨上皮电压、电阻或离子通透性在基线时没有差异。高钙血症后，WT小鼠的跨上皮电阻增加，钙通透性显著降低，但-小鼠没有，镁通透性仅有轻微改变，跨上皮电压没有变化。
在高钙血症小鼠中，TAL中缺乏CaSR可阻止尿钙排泄增加。CaSR特异性调节TAL的细胞旁通透性，尤其是对钙的通透性。
