Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark.
Department of Nephrology, Odense University Hospital, Odense, Denmark.
Curr Opin Nephrol Hypertens. 2024 Jul 1;33(4):433-440. doi: 10.1097/MNH.0000000000000998. Epub 2024 May 1.
Activation of the calcium-sensing receptor (CASR) in the parathyroid gland suppresses the release of parathyroid hormone (PTH). Furthermore, activation of the renal CASR directly increases the urinary excretion of calcium, by inhibiting transepithelial calcium transport in the nephron. Gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia 1 (ADH1), with inappropriately low PTH levels and hypocalcemia, indicative of excessive activation of the parathyroid CASR. However, hypercalciuria is not always observed. The reason why the manifestation of hypercalciuria is not uniform among ADH1 patients is not well understood.
Direct activation of the CASR in the kidney has been cumbersome to study, and an indirect measure to effectively estimate the degree of CASR activation following chronic hypercalcemia or genetic gain-of-function CASR activation has been lacking. Studies have shown that expression of the pore-blocking claudin-14 is strongly stimulated by the CASR in a dose-dependent manner. This stimulatory effect is abolished after renal Casr ablation in hypercalcemic mice, suggesting that claudin-14 abundance may gauge renal CASR activation. Using this marker has led to unexpected discoveries regarding renal CASR activation.
These new studies have informed on renal CASR activation thresholds and the downstream CASR-regulated calcium transport mechanisms.
甲状旁腺钙敏感受体（CASR）的激活可抑制甲状旁腺激素（PTH）的释放。此外，肾 CASR 的激活可通过抑制肾单位中的跨上皮钙转运，直接增加尿钙排泄。CASR 基因的功能获得性突变导致常染色体显性低钙血症 1（ADH1），其 PTH 水平降低和低钙血症，表明甲状旁腺 CASR 过度激活。然而，并非所有患者均出现高钙尿症。ADH1 患者中高钙尿症的表现不一致的原因尚不清楚。
直接激活肾脏中的 CASR 一直难以研究，且缺乏一种有效评估慢性高钙血症或遗传功能获得性 CASR 激活后 CASR 激活程度的间接测量方法。研究表明，CASR 可剂量依赖性地强烈刺激孔道阻断性紧密连接蛋白-14 的表达。在高钙血症小鼠中肾 Casr 消融后，这种刺激作用被消除，提示紧密连接蛋白-14 的丰度可能可以评估肾 CASR 的激活。使用这一标志物使人们对肾 CASR 激活的阈值以及下游 CASR 调节的钙转运机制有了新的认识。
这些新的研究为肾 CASR 激活的阈值和下游 CASR 调节的钙转运机制提供了信息。
