FGF23 promotes renal calcium reabsorption through the TRPV5 channel

• Published in: The EMBO journal 2014-02, Vol.33 (3), p.229-246
• Main Authors: Andrukhova, Olena, Smorodchenko, Alina, Egerbacher, Monika, Streicher, Carmen, Zeitz, Ute, Goetz, Regina, Shalhoub, Victoria, Mohammadi, Moosa, Pohl, Elena E, Lanske, Beate, Erben, Reinhold G
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; Calcium channels; calcium homeostasis; Cell Membrane - metabolism; EMBO20; EMBO37; Fibroblast Growth Factor-23; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Glucuronidase; Hormones; Immediate-Early Proteins - metabolism; Kidney - metabolism; Kidneys; Klotho; Klotho Proteins; Male; Membranes; Mice; Mice, Knockout; Protein Serine-Threonine Kinases - metabolism; Receptors, Cell Surface - metabolism; renal calcium reabsorption; Rodents; Signal Transduction; transient receptor potential vanilloid‐5; TRPV Cation Channels - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201284188

αKlotho is thought to activate the epithelial calcium channel Transient Receptor Potential Vanilloid‐5 (TRPV5) in distal renal tubules through its putative glucuronidase/sialidase activity, thereby preventing renal calcium loss. However, αKlotho also functions as the obligatory co‐receptor for fibroblast growth factor‐23 (FGF23), a bone‐derived phosphaturic hormone. Here, we show that renal calcium reabsorption and renal membrane abundance of TRPV5 are reduced in Fgf23 knockout mice, similar to what is seen in αKlotho knockout mice. We further demonstrate that αKlotho neither co‐localizes with TRPV5 nor is regulated by FGF23. Rather, apical membrane abundance of TRPV5 in renal distal tubules and thus renal calcium reabsorption are regulated by FGF23, which binds the FGF receptor‐αKlotho complex and activates a signaling cascade involving ERK1/2, SGK1, and WNK4. Our data thereby identify FGF23, not αKlotho, as a calcium‐conserving hormone in the kidney. Synopsis αKlotho acts as a co‐receptor for the phosphaturic hormone FGF23 but can also activate TRPV5 channels via altered glycosylation patterns. Similar defects in αKlotho‐ and FGF23‐deficient mice along with FGF23‐controlled TRPV5 membrane localization suggest that the former pathway reflects αKlotho's in vivo function in renal calcium reabsorption. FGF23 activates SGK1 and WNK4 in renal distal tubules through its canonical, αKlotho‐ and FGF receptor‐dependent signaling pathway. FGF23 regulates membrane transport and activity of epithelial calcium channel TRPV5 via SGK1 and WNK4, augmenting distal renal tubular calcium reabsorption. FGF23 is not only a phosphaturic, but also a calcium‐conserving hormone. Graphical Abstract αKlotho acts as a co‐receptor for the phosphaturic hormone FGF23 but can also activate TRPV5 channels via altered glycosylation patterns. Similar defects in αKlotho‐ and FGF23‐deficient mice along with FGF23‐controlled TRPV5 membrane localization suggest that the former pathway reflects αKlotho's in vivo function in renal calcium reabsorption.