title: Effects of the Administration of 25(OH) Vitamin D3 in an Experimental Model of Chronic Kidney Disease in Animals Null for 1-Alpha-Hydroxylase.
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.
authors.affiliation: Vascular and Renal Translational Research Group, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Torremadé
authors.affiliation: Vascular and Renal Translational Research Group, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.affiliation: Calcium Research Laboratory, McGill University Health Center and Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Vascular and Renal Translational Research Group, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: Vascular and Renal Translational Research Group, REDinREN del ISCIII, IRBLleida, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: José M
authors.identifier: http://orcid.org/0000-0003-1343-0184
authors.initials: JM
authors.lastname: Valdivielso
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002112:Calcifediol / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D007668:Kidney / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy*
chemical_list: D010281:Parathyroid Hormone; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol; D002118:Calcium