Kidney deletions of Cyp27b1 fail to reduce serum 1,25(OH)2D3

Vitamin D metabolism is controlled through the kidney mitochondrial P450 enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) that activate and degrade the endocrine vitamin D hormone (1,25(OH)₂D₃), respectively. We recently demonstrated that extrarenal cells can make 1,25(OH)₂D₃ with adequate vitamin D supplementation by targeted mass spectrometry imaging in our Cyp27b1 kidney enhancer deletion mouse model that lacks circulating 1,25(OH)₂D₃ (M1/M21-DIKO mouse). Based on these observations, we selectively deleted Cyp27b1 (Cyp27b1^fl/fl) from the mouse kidney using the Six2- and Pax8-cre drivers that target tubule and nephron development to see if we could recapitulate the remarkable phenotype of the M1/M21-DIKO mice. While Six2-cre/Cyp27b1^fl/fl mice had a mild phenotype, Pax8-cre/Cyp27b1^fl/fl mice had a marked elevation of parathyroid hormone and a reduction in bone mineral density. The vitamin D metabolic profile in the Pax8-cre/Cyp27b1^fl/fl clearly indicated a dysfunction in the CYP24A1 enzyme with reductions in 24,25(OH)₂D₃ and 25(OH)D₃-26,23-lactone with an accompanying elevation of 25(OH)D₃. However, despite these compensatory reductions in CYP24A1 derived metabolites and apparent deletion of Cyp27b1 in the kidney, the 1,25(OH)₂D₃ levels were not changed from wildtype in either mouse. Like 24,25(OH)₂D₃, the 1,24,25(OH)₃D₃ levels were also reduced. These data highlight the robust homeostatic mechanisms to salvage 1,25(OH)₂D₃, point towards potential compensatory mechanisms of 1,25(OH)₂D₃ production from non-kidney tissues, and reinforce the utility of the M1/M21-DIKO model as a non-global deletion of Cyp27b1 with reductions in serum 1,25(OH)₂D₃ to be used to understand the complexity of vitamin D metabolism in health and inflammatory disease.