Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
Laboratory Animal Center, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
Sci Rep. 2018 May 2;8(1):6917. doi: 10.1038/s41598-018-25087-3.
Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. αKlotho, a putative enzyme possessing β-glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D-metabolizing enzymes are known to localize in proximal tubules. To clarify the direct function of FGF23 on proximal tubules, we ablated αKlotho or Fgfr1-4 genes specifically from these tubules using the Cre-loxP-mediated genetic recombination. Both conditional knockout mouse lines showed similar phenotypes that resembled those of systemic αKlotho or Fgf23 knockout mice. Compared with control mice, they showed significantly elevated levels of plasma phosphate, FGF23 and 1,25-dihydroxyvitamin D, ectopic calcification in the kidney and aging-related phenotypes like growth retardation, osteoporosis and shortened lifespan. These findings suggest that the primary function of FGF23 on mineral metabolism is mediated through αKlotho/FGFR co-receptors expressed in proximal tubular cells, and that the putative enzymatic function of αKlotho in the proximal tubule has a minor role in systemic mineral metabolism.
成纤维细胞生长因子 23（FGF23）在肾脏中对磷酸盐处理和维生素 D 代谢起着关键作用。然而，肾脏中 FGF23 的效应细胞仍不清楚。αKlotho 是一种假定的酶，具有β-葡萄糖醛酸酶活性，也是 FGF23 与成纤维细胞生长因子受体（FGFRs）结合的许可共受体，在远曲小管中表达最丰富，而在近端小管中表达适度。已知磷酸盐稳态和维生素 D 代谢酶的关键分子参与者定位于近端小管。为了阐明 FGF23 对近端小管的直接作用，我们使用 Cre-loxP 介导的基因重组特异性地从这些小管中敲除αKlotho 或 Fgfr1-4 基因。这两种条件性敲除小鼠品系表现出相似的表型，类似于全身αKlotho 或 Fgf23 敲除小鼠。与对照小鼠相比，它们的血浆磷酸盐、FGF23 和 1,25-二羟维生素 D 水平显著升高，肾脏异位钙化以及与衰老相关的表型，如生长迟缓、骨质疏松和寿命缩短。这些发现表明，FGF23 在矿物质代谢中的主要功能是通过在近端肾小管细胞中表达的αKlotho/FGFR 共受体介导的，而αKlotho 在近端小管中的假定酶功能在全身矿物质代谢中作用较小。
