Date Published: January 20, 2017
Publisher: Public Library of Science
Author(s): Noelia Torremadé, Milica Bozic, David Goltzman, Elvira Fernandez, José M. Valdivielso, Jaap A. Joles.
The final step in vitamin D activation is catalyzed by 1-alpha-hydroxylase (CYP27B1). Chronic kidney disease (CKD) is characterized by low levels of both 25(OH)D3 and 1,25(OH)2D3 provoking secondary hyperparathyroidism (2HPT). Therefore, treatments with active or native vitamin D compounds are common in CKD to restore 25(OH)D3 levels and also to decrease PTH. This study evaluates the dose of 25(OH)D3 that restores parathyroid hormone (PTH) and calcium levels in a model of CKD in CYP27B1-/- mice. Furthermore, we compare the safety and efficacy of the same dose in CYP27B1+/+ animals. The dose needed to decrease PTH levels in CYP27B1-/- mice with CKD was 50 ng/g. That dose restored blood calcium levels without modifying phosphate levels, and increased the expression of genes responsible for calcium absorption (TRPV5 and calbindinD- 28K in the kidney, TRPV6 and calbindinD-9k in the intestine). The same dose of 25(OH)D3 did not modify PTH in CYP27B1+/+ animals with CKD. Blood calcium remained normal, while phosphate increased significantly. Blood levels of 25(OH)D3 in CYP27B1-/- mice were extremely high compared to those in CYP27B1+/+ animals. CYP27B1+/+ animals with CKD showed increases in TRPV5, TRPV6, calbindinD-28K and calbindinD-9K, which were not further elevated with the treatment. Furthermore, CYP27B1+/+ animals displayed an increase in vascular calcification. We conclude that the dose of 25(OH)D3 effective in decreasing PTH levels in CYP27B1-/- mice with CKD, has a potentially toxic effect in CYP27B1+/+ animals with CKD.
Vitamin D is a major regulator of Ca2+ and phosphate homeostasis and it is essential for proper development and maintenance of bones. The active form of vitamin D, 1,25(OH)2D3, is synthesized from its precursor 25OHD3 by the 25-hydroxyvitamin-D-1α-hydroxylase (1-α-hydroxylase; CYP27B1). Mutations in the CYP27B1 gene cause severe disorders of Ca2+ homeostasis, including vitamin D-dependent rickets type I (VDDRI).
In the present paper we demonstrate that the suppression of PTH in an experimental model of CKD can be achieved directly by 25OHD3 without its conversion to 1,25(OH)2D3, but the blood levels necessary to attain the effect are extremely high. Furthermore, although the effect is undoubtedly due to an effect of 25OHD3, it is unclear whether this effect is directly stimulating VDR in the parathyroid gland or indirectly by increasing calcium absorption in the intestine. Thus, the administration of 50 ng/g of 25OHD3 in KO NX animals decreased serum PTH to levels below the ones observed in the same animals with normal renal function. This inhibition was achieved with blood levels of 25OHD3 around 7 times higher than the normal levels and in parallel to a normalization of blood calcium levels. Thus, the decrease of PTH could be attained by a combination of normalization of blood calcium levels and direct activation of VDR by 25OHD3 in the parathyroid gland.