Molecular regulation of renal 125(OH)2D production by Fibroblast Growth Factor23

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 1,25-dihydroxyvitamin D (1,25(OH)2 D) is a critical determinant of calcium (Ca) and phosphorus (Pi) metabolism and is essential for bone growth and mineralization. Renal mitochondrial 1-alpha hydroxylase (P450c1a) enzyme is the rate limiting step in the synthesis of the active form of vitamin D -1,25(OH)2D, and the hormone is inactivated by the enzyme 24-hydroxylase (P450c24) in the kidney and other tissues. Serum 1,25 OH)2D concentration is regulated by PTH, Ca, Pi and 1,25(OH)2 D primarily by regulation of the enzymes responsible for its synthesis and degradation. Disorders of vitamin D metabolism causes rickets in children and osteomalacia in adults due to abnormal bone mineralization. Fibroblast Growth Factor-23 (FGF- 23) is a circulating peptide, recently identified in a group of hypophosphatemic syndromes such as X-linked hypophosphatemic rickets (XLH) that is characterized by severe renal phosphate wasting, inappropriately low serum 1,25(OH)2D concentrations, and skeletal demineralization. FGF-23 has been shown to decrease serum 1,25(OH)2D concentrations by suppressing renal 1,25(OH)2D production. Evidence is emerging that FGF-23 is an important physiologic regulator of Pi, vitamin D, and bone metabolism, independent of PTH, and may play a role in abnormal bone and mineral homeostasis in chronic kidney disease. Much remains to be learnt about the actions of FGF-23 and the mechanisms by which it regulates vitamin D metabolism. We hypothesize that FGF-23 acts directly on the kidney to regulate P450c1a and P450c24 gene expression and thereby regulates renal 1,25(OH)2 D production. To test this hypothesis, we propose the following -Aims1&2: Determine the transcriptional and post-transcriptional mechanisms by which FGF-23 regulates P450c1a and P450c24 gene expression in human and mouse renal proximal tubule cell cultures. Aim 3: Characterize the signaling mechanisms by which FGF-23 regulates vitamin D metabolism in renal tubular cells in vitro and in wild type, Hyp (a murine model of XLH), and fgf-23 transgenic mice in vivo. This research proposal is aimed at advancing our current knowledge about vitamin D production in the kidney and provide novel insights in disease conditions where vitamin D synthesis is abnormal. Understanding how various factors control vitamin D production will provide new therapeutic strategies to treat bone disease in children with rickets, and in patients suffering from kidney failure.