Renal Vdr deletion drives urinary calcium loss with intestinal and skeletal compensatory responses

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are endocrine regulators of calcium homeostasis. To assess the contribution of 1,25(OH)2D3-mediated renal calcium reabsorption to systemic calcium balance and bone homeostasis, we generated mice with a targeted deletion of the vitamin D receptor (VDR) in renal tubules (VdrRen- mice), weaned them onto diets containing 1% or 0.2% calcium, and examined their phenotype at 8 weeks of age. Despite higher urinary calcium excretion, VdrRen- mice maintained normocalcemia, suggesting compensatory adaptations in the intestine and bone. Transcript levels of intestinal calcium transporters were higher in male VdrRen- mice, particularly under dietary calcium restriction, whereas genotype-dependent changes were minimal in females. Bone mass was lower in VdrRen- mice of both sexes than in diet-matched wild-type littermates. On the 1% calcium diet, changes in calcium absorption and bone remodeling occurred without alterations in serum PTH and 1,25(OH)2D3, while FGF23 was elevated. Calcium restriction increased circulating PTH, 1,25(OH)2D3, and FGF23, with additional genotype- and sex-dependent effects on 1,25(OH)2D3 and FGF23. Together, these findings demonstrate that renal VDR signaling contributes to serum calcium conservation, and its loss triggers sexually dimorphic compensatory mechanisms in intestinal calcium absorption, especially under conditions of dietary calcium restriction.