Unidad de Investigación UNAM-INCICh, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan.
Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico.
Curr Opin Nephrol Hypertens. 2023 Sep 1;32(5):451-457. doi: 10.1097/MNH.0000000000000915. Epub 2023 Jul 7.
Regulation of the sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) plays a crucial role in renal salt handling. The calcium-sensing receptor (CaSR) has been shown to activate NCC through the WNK4-SPAK pathway, which is independent of the Renin-Angiotensin-Aldosterone system. In this review, we examine new information about the mechanism of how the CaSR regulates NCC through the WNK4-SPAK pathway and its physiological and therapeutic implications.
The activation of CaSR in TALH cells during hypercalcemia inhibits NKCC2 and ROMK activity, reducing paracellular Ca2+ reabsorption but decreasing salt reabsorption. This pathway enables NaCl reabsorption in the DCT while promoting Ca2+ excretion. CaSR activation in the apical DCT stimulates a signaling pathway involving PKC, WNK4, and SPAK, which increases NCC activation to recover the NaCl not reabsorbed in TAHL. Glucose or fructose acting as calcimimetics enhance apical CaSR sensitivity, increasing NCC activity, which contribute to the mechanism of hypertension prevalence in diabetic patients or in those with high fructose consumption.
These findings reveal the importance of the CaSR-mediated activation of the WNK4-SPAK pathway in regulating salt and calcium homeostasis and its potential as a therapeutic target for hypertension and related diseases.
综述目的：调控远曲小管（DCT）中氯化钠共转运蛋白（NCC）的活性在肾脏盐处理中起着至关重要的作用。钙敏感受体（CaSR）已被证明通过 WNK4-SPAK 途径激活 NCC，而该途径独立于肾素-血管紧张素-醛固酮系统。在这篇综述中，我们研究了 CaSR 通过 WNK4-SPAK 途径调节 NCC 的机制的新信息及其生理和治疗意义。
最新发现：高钙血症期间 TALH 细胞中 CaSR 的激活抑制 NKCC2 和 ROMK 活性，减少细胞旁 Ca2+重吸收，但减少盐重吸收。该途径使 DCT 中的 NaCl 重吸收，同时促进 Ca2+排泄。DCT 顶端的 CaSR 激活涉及 PKC、WNK4 和 SPAK 的信号通路，增加 NCC 的激活以恢复在 TAHL 中未重吸收的 NaCl。葡萄糖或果糖作为钙敏感受体激动剂增强了顶端 CaSR 的敏感性，增加了 NCC 的活性，这有助于解释糖尿病患者或高果糖摄入者中高血压流行的机制。
总结：这些发现揭示了 CaSR 介导的 WNK4-SPAK 途径在调节盐和钙稳态中的重要性及其作为高血压和相关疾病治疗靶点的潜力。
