Regulation of vitamin D metabolizing enzymes in murine renal and extrarenal tissues by dietary phosphate, FGF23, and 1,25(OH)(2)D(3)

BACKGROUND: The 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) together with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulates calcium (Ca(2+)) and phosphate (Pi) homeostasis, 1,25(OH)(2)D(3) synthesis is mediated by hydroxylases of the cytochrome P450 (Cyp) family. Vitamin D is first modified in the liver by the 25-hydroxylases CYP2R1 and CYP27A1 and further activated in the kidney by the 1α-hydroxylase CYP27B1, while the renal 24-hydroxylase CYP24A1 catalyzes the first step of its inactivation. While the kidney is the main organ responsible for circulating levels of active 1,25(OH)(2)D(3), other organs also express some of these enzymes. Their regulation, however, has been studied less. METHODS AND RESULTS: Here we investigated the effect of several Pi-regulating factors including dietary Pi, PTH and FGF23 on the expression of the vitamin D hydroxylases and the vitamin D receptor VDR in renal and extrarenal tissues of mice. We found that with the exception of Cyp24a1, all the other analyzed mRNAs show a wide tissue distribution. High dietary Pi mainly upregulated the hepatic expression of Cyp27a1 and Cyp2r1 without changing plasma 1,25(OH)(2)D(3). FGF23 failed to regulate the expression of any of the studied hydroxylases at the used dosage and treatment length. As expected, renal mRNA expression of Cyp27b1 was reduced and Cyp24a1 was increased in response to 1,25(OH)(2)D(3) treatment. However, the 25-hydroxylases were rather unaffected by 1,25(OH)(2)D(3) treatment. CONCLUSIONS: The analyzed vitamin D hydroxylases are regulated in a tissue and treatment-specific manner.