Abstract
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.
Highlights
Vitamin D is a major regulator of Ca2+ and phosphate homeostasis and it is essential for proper development and maintenance of bones.[1]
Levels of parathyroid hormone (PTH), which are very high in KO mice, increased even more after the nephrectomy and were partially corrected in KO NX mice after the treatment with 25OHD3 (Fig 1D). 25OHD3 had no effect on elevated PTH levels in WT NX mice (Fig 1D)
In the present paper we demonstrate that the suppression of PTH in an experimental model of Chronic kidney disease (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
Summary
Vitamin D is a major regulator of Ca2+ and phosphate homeostasis and it is essential for proper development and maintenance of bones.[1] The active form of vitamin D, 1,25 (OH)2D3, is synthesized from its precursor 25OHD3 by the 25-hydroxyvitamin-D-1α-. Chronic kidney disease- mineral and bone disorder (CKD-MBD) is a common problem in patients with kidney disease. It is characterized by abnormal levels of calcium (Ca) and phosphate (P) and biochemical alterations of mineral metabolism related hormones, alongside vascular calcification. Among those biochemical alterations, low levels of active vitamin D metabolites are of paramount importance.[4] To treat CKD-MBD related complications, vitamin D compounds have been widely used. Vitamin D analogs were developed in order to suppress PTH secretion with a minimal calcemic action. [6,7,8]
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