Regulation of renal vitamin D metabolism

The activating enzymatic step in vitamin D metabolism resides in the ability of the 25(OH)D3-1α-hydroxylase enzyme to generate 1α,25(OH)2D3 from 25(OH)D3. The levels of 1,25(OH)2D3 in the body control a wide-ranging set of physiologic functions from calcium regulation through an immune response. In normal, healthy individuals, the circulating levels of 1,25(OH)2D3 are almost exclusively made in the kidney, with smaller, autocrine, intracrine, or paracrine actions made in cells of nonrenal origins. The gene encoding this metabolic enzyme, Cyp27b1, is under exquisite control from the mineralotropic hormones of PTH, FGF23, and 1,25(OH)2D3 itself in the kidney. These hormones also control the levels of the catabolic enzyme 24-hydroxylase through its encoding gene, Cyp24a1, in a reciprocal fashion in the kidney. The goal of this chapter is to describe this reciprocal hormonal regulation of both Cyp27b1 and Cyp24a1 in the kidney and to present the discovery of a complex genomic mechanism through tissue-specific genomic enhancers.