PURPOSE OF REVIEW: The calcium-sensing receptor (CASR) is a principal regulator of calcium balance. In the kidney, it directly modulates calcium reabsorption in the thick ascending limb (TAL). This review focuses on the CASR in TAL, its role in regulating renal calcium transport and hence systemic calcium homeostasis. RECENT FINDINGS: Functional studies demonstrate that hypercalcemia-induced increases in urinary calcium excretion depend on renal CASR signaling, primarily through reduced paracellular calcium permeability in the TAL. Loss of the renal Casr in mice impairs urinary calcium excretion in conditions of hypercalcemia. Microperfusion shows reduced calcium permeability in cortical TALs from hypercalcemic wildtype mice, a response absent in Casr-deficient mice. CASR activation upregulates claudin-14 (CLDN14), a tight junction protein that selectively blocks paracellular divalent cation reabsorption. Single cell RNA-seq and protein expression studies reveal substantial TAL cell-type heterogeneity, identifying distinct transporter- and claudin- expressing populations. This mosaic organization of paracellular pathways provides a framework for understanding TAL-specific regulation of renal calcium handling. SUMMARY: The TAL CASR acts as a sensor of blood calcium and adjusts paracellular transport by reducing tight junction permeability. While protective against hypercalcemia, sustained activation may promote hypercalciuria and nephrolithiasis.
Bogdanovic et al. (Thu,) studied this question.
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