[Renal bioactivation of vitamin D and its key modulators]

Renal tubular cells bio-activates vitamin D, where 25-hydroxyvitamin D(3) (25D) is supplied to 1alpha hydroxylase, mitochondrial enzyme through apical endocytosis of 25D-binding protein complex. This intracellular trafficking depends on multiple endocytic receptor megalin. Megalin-null mouse harbors similar bone phenotype to vitamin D deficiency. 1alpha hydroxylase plays a key role for final activation of vitamin D, which is canonically regulated by parathyroid hormone (PTH) . Precise transcriptional regulation of this mitochondrial enzyme renders key downstream modulators : CCAAT enhancer binding protein (C/EBP) beta in mouse, vitamin D interacting repressor and vitamin D receptor in human. Fibroblast growth factor (FGF) 23, circulating phosphaturic hormone, has a counter-regulatory property against vitamin D bio-activation. FGF23 strongly inhibits 1alpha hydroxylase expression and its transcriptional activity. Recent study has demonstrated that FGF23 binds FGF receptor 1/klotho complex in tubular cells. Further studies will allow us to better understand the whole mechanism that regulates 1alpha hydroxylation in renal tubular cells by focusing on key molecules: C/EBPbeta, VDR, FGF23, klotho.