Key Points

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.

Background

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.

Methods

Experimental hypercalcemia was induced using a vitamin D analog (dihydrotachysterol) in mice with Ksp-Cre–dependent deletion of the Casr (Ksp-Casr) 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 in vitro tubule microperfusion were performed in both sexes.

Results

Ksp-Cre–driven Casr 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 Ksp-Casr mice. However, although WT mice developed hypercalciuria, this response was absent in Ksp-Casr mice. Urinary excretion of magnesium and other electrolytes did not differ between hypercalcemic WT and Ksp-Casr 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 Ksp-Casr mice, with only minor alterations in magnesium permeability and no changes in transepithelial voltage.

Conclusions

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.