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.