The full-length calcium-sensing receptor dampens the calcemic response to 1α,25(OH)₂ vitamin D₃ in vivo independently of parathyroid hormone

Abstract

1Alpha,25(OH)(2) vitamin D(3) [1,25(OH)(2)D(3)] increases serum Ca(2+) concentration in vivo, an action counteracted by activation of the Ca(2+)-sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca(2+) excretion. Relatively little is known of the role the CaSR plays in this response through its potentially direct actions in kidney, gut, and bone independently of PTH. We report PTH-independent roles of the CaSR in modulating the response to exogenous 1,25(OH)(2)D(3) in mice with targeted disruption of both the CaSR and PTH genes (C(-)P(-)) compared with that in mice with disruption of the PTH gene alone (C(+)P(-)) or wild-type mice (C(+)P(+)). After intraperitoneal injection of 0.5 ng/g body wt 1,25(OH)(2)D(3), peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca(2+) in C(-)P(-) mice than in the other genotypes on a Ca(2+)-replete diet that was attenuated by a Ca(2+)-deficient diet and pamidronate, 2) increased urinary Ca(2+)-to-creatinine ratios (UCa/Cr) in the C(+)P(-) and C(+)P(+) mice but a lowered ratio in the C(-)P(-) mice on a Ca(2+)-replete diet, and 3) no increase in calcitonin (CT) secretion in the C(+)P(+) and C(+)P(-) mice and a small increase in the C(-)P(-) mice. PTH deficiency had the anticipated effects on the expression of key genes involved in Ca(2+) transport at baseline in the duodenum and kidney, and injection of 1,25(OH)(2)D(3) increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca(2+) seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)(2)D(3) in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)(2)D(3)-mediated gut Ca(2+) absorption and decreased renal Ca(2+) excretion, without any differences in bone-related release of Ca(2+) or CT secretion among the three genotypes that could explain the differences in their calcemic responses.

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

“…We then treated TPTX, PTH-supplemented rats with an antibone-resorptive agent (2.5 μg pamidronate.g BW -1 , daily for 4 days prior to the experiment); this treatment significantly inhibits bone resorption in rats and mice as validated in previous studies (9,12,13). As shown in Figure 4, at baseline, both groups of rats exhibited the same blood ionized Ca concentration and urinary Ca excretion.…”

“…To circumvent these drawbacks, researchers have bred Casr -/-mice with mice lacking parathyroid glands (7) or unable to synthesize PTH (8). In studies in the latter model, it was proposed that extraparathyroid CaSR was useful for narrowing the variability of blood and urine Ca (8) and dampening the calcemic response to exogenous PTH administration, high-Ca diet, or calcitriol injections (9,10). However, these studies did not aim at providing direct evidence that extraparathyroid Ca is important in determining the value of steady-state blood Ca concentration when PTH is either absent or invariant.…”

“…Data from these models suggest that the extraparathyroid CaSR may limit the variability of blood and urine Ca (8). Moreover, studies in mice have shown that the CaSR in kidney and/or C cells plays an important homeostatic role in the defense against hypercalcemia induced by oral Ca overload or by PTH or calcitriol administration (9,10). However, these experiments did not aim at providing evidence that extraparathyroid CaSR plays a significant role as a direct determinant of blood Ca concentration.…”

Physiology and pathophysiology of the calcium-sensing receptor in the kidney

“…Studies carried out in proximal tubule-derived cell lines also suggest that 1␣-hydroxylase activity is inhibited in the presence of high Ca 2ϩ (97). Recent studies carried out with a murine model in which the full-length CaSR has been ablated (and that expresses an exon 5-less splice variant, therefore representing a "hypomorph" in some tissues) have shown that CaSR dampens the response to 1,25(OH) 2 D 3 independently of PTH actions (39). Thus CaSR exerts a tight control on circulating 1,25(OH) 2 D 3 both at the level of its synthesis (in the proximal tubule) and in modulating its effects (specifically, on calcium reabsorption by the distal tubule, see below).…”

Calcium-sensing receptor gene polymorphisms in patients with calcium urolithiasis: a systematic review

“…17 In a study carried out with a murine model in which the full-length CaSR has been ablated have shown that CaSR diminishes the response to 1,25(OH) 2 D 3 independently of PTH actions. 18 Thus CaSR exerts a tight control on circulating 1,25(OH) 2 D 3 both at the level of its synthesis (in the proximal tubule) and in modulating its effects. Conversely, 1,25(OH) 2 D 3 , 19 PTH, and dietary phosphate modulate both CaSR gene and protein expression in the proximal tubule, 20 suggesting the existence of a local feedback loop for the regulation of Ca 2+ and P i excretion independently of systemic changes in calciotropic hormones.…”