Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.
Biochem Biophys Res Commun. 2011 Oct 28;414(3):557-62. doi: 10.1016/j.bbrc.2011.09.117. Epub 2011 Oct 1.
Isoforms of the mammalian klotho protein serve as membrane co-receptors that regulate renal phosphate and calcium reabsorption. Phosphaturic effects of klotho are mediated in cooperation with fibroblast growth factor receptor-1 and its FGF23 ligand. The vitamin D receptor and its 1,25-dihydroxyvitamin D(3) ligand are also crucial for calcium and phosphate regulation at the kidney and participate in a feedback loop with FGF23 signaling. Herein we characterize vitamin D receptor-mediated regulation of klotho mRNA expression, including the identification of vitamin D responsive elements (VDREs) in the vicinity of both the mouse and human klotho genes. In keeping with other recent studies of vitamin D-regulated genes, multiple VDREs control klotho expression, with the most active elements located at some distance (-31 to -46 kb) from the klotho transcriptional start site. We therefore postulate that the mammalian klotho gene is up-regulated by liganded VDR via multiple remote VDREs. The phosphatemic actions of 1,25-dihydroxyvitamin D(3) are thus opposed via the combined phosphaturic effects of FGF23 and klotho, both of which are upregulated by the liganded vitamin D receptor.
哺乳动物 klotho 蛋白的同工型作为膜共受体，调节肾脏磷酸盐和钙的重吸收。klotho 的降磷作用通过与成纤维细胞生长因子受体-1 及其 FGF23 配体协同介导。维生素 D 受体及其 1,25-二羟维生素 D(3)配体对于肾脏的钙和磷酸盐调节也至关重要，并与 FGF23 信号转导形成反馈回路。在此，我们描述了维生素 D 受体介导的 klotho mRNA 表达调控，包括鉴定小鼠和人 klotho 基因附近的维生素 D 反应元件(VDREs)。与最近其他关于维生素 D 调节基因的研究一致，多个 VDRE 控制 klotho 的表达，最活跃的元件位于 klotho 转录起始位点的一定距离(-31 至-46 kb)处。因此，我们假设配体结合的 VDR 通过多个远程 VDRE 上调哺乳动物 klotho 基因。1,25-二羟维生素 D(3)的降磷作用通过 FGF23 和 klotho 的联合降磷作用来对抗，这两者都被结合的维生素 D 受体上调。
