The Calcium-Sensing Receptor in the Thick Ascending Limb and the Renal Response to Hypercalcemia

Background: The parathyroid calcium-sensing receptor (CASR) controls the release of parathyroid hormone (PTH) 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 PTH 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 remains to be fully elucidated. Methods: Experimental hypercalcemia was induced using the Vitamin D analog (Dihydrotachysterol, DHT) in mice with Ksp -Cre dependent deletion of the Casr ( Ksp - Casr ) in kidney with Cre negative littermates (WT) serving as controls. 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. 3 days of DHT administration induced hypercalcemia in both WT and Ksp - Casr mice. However, while 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 the transepithelial voltage, resistance, or ion permeabilities. Following 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, 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.