Abstract
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)(2)D(3)), respectively. We recently demonstrated that extrarenal cells can make 1,25(OH)(2)D(3) with adequate vitamin D supplementation by targeted mass spectrometry imaging in our Cyp27b1 kidney enhancer deletion mouse model that lacks circulating 1,25(OH)(2)D(3) (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)(2)D(3) and 25(OH)D(3)-26,23-lactone with an accompanying elevation of 25(OH)D(3). However, despite these compensatory reductions in CYP24A1 derived metabolites and apparent deletion of Cyp27b1 in the kidney, the 1,25(OH)(2)D(3) levels were not changed from wildtype in either mouse. Like 24,25(OH)(2)D(3), the 1,24,25(OH)(3)D(3) levels were also reduced. These data highlight the robust homeostatic mechanisms to salvage 1,25(OH)(2)D(3), point towards potential compensatory mechanisms of 1,25(OH)(2)D(3) 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)(2)D(3) to be used to understand the complexity of vitamin D metabolism in health and inflammatory disease.