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Dietary Phosphorus Transcriptionally Regulates 25-Hydroxyvitamin D-1-Hydroxylase Gene Expression in the Proximal Renal Tubule

Departments of Pediatrics (M.Y.H.Z., X.W., J.T.W., W.L.M., A.A.P.), Medicine (A.A.P.), Obstetrics, Gynecology, and Reproductive Sciences (N.A.C., S.H.M.), and Pathology (J.L.O.), University of California, San Francisco, California 94143; and Departments of Pediatrics and Human Genetics, McGill University and Montreal Children’s Hospital Research Institute (H.S.T.), Montréal, Québec, Canada

Address all correspondence and requests for reprints to: Anthony A. Portale, M.D., Room U-585, University of California, 533 Parnassus Avenue, San Francisco, California 94143-0748. E-mail: aportale{at}peds.ucsf.edu

Synthesis of the hormone 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, occurs in the kidney and is catalyzed by the mitochondrial cytochrome P450 enzyme, 25-hydroxyvitamin D-1-hydroxylase (1-hydroxylase). We sought to characterize the effects of changes in dietary phosphorus on the kinetics of renal mitochondrial 1-hydroxylase activity and the renal expression of P450c1 and P450c24 mRNA, to localize the nephron segments involved in such regulation, and to determine whether transcriptional mechanisms are involved. In intact mice, restriction of dietary phosphorus induced rapid, sustained, approximately 6- to 8-fold increases in renal mitochondrial 1-hydroxylase activity and renal P450c1 mRNA abundance. Immunohistochemical analysis of renal sections from mice fed the control diet revealed the expression of 1-hydroxylase protein in the proximal convoluted and straight tubules, epithelial cells of Bowman’s capsule, thick ascending limb of Henle’s loop, distal tubule, and collecting duct. In mice fed a phosphorusrestricted diet, immunoreactivity was significantly increased in the proximal convoluted and proximal straight tubules and epithelial cells of Bowman’s capsule, but not in the distal nephron. Dietary phosphorus restriction induced a 2-fold increase in P450c1 gene transcription, as shown by nuclear run-on assays. Thus, the increase in renal synthesis of 1,25-dihydroxyvitamin D induced in normal mice by restricting dietary phosphorus can be attributed to an increase in the renal abundance of P450c1 mRNA and protein. The increase in P450c1 gene expression, which occurs exclusively in the proximal renal tubule, is due at least in part to increased transcription of the P450c1 gene.

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