**4.2.2 FGF23**

FGF23 is a 32-kDa protein that is secreted mainly by bone osteocytes (Liu et al. 2006). Administration of FGF23 to mice decreases the renal expression of both NaPi-IIa and NaPi-IIc and induces hypophosphatemia predominantly via FGF receptor 1 (Gattineni et al. 2009). FGF23 also suppresses 1,25(OH)2D3 by inhibiting 1α-hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D3 [25(OH)D3] to 1,25(OH)2D3, and by stimulating 24 hydroxylase (CYP24), which converts 1,25(OH)2D3 to inactive metabolites in PTCs (Shimada et al. 2004). Increased FGF23 appears to play a causative role in the abnormal renal phosphate handling and vitamin D3 metabolism of rats with CKD, leading to the development of secondary hyperparathyroidism and increased production of PTH (Hasegawa et al. 2010). The ternary complex of klotho-FGF23-FGF receptor in distal convoluted tubules (DCTs) has been thought to be a prerequisite for the exertion of FGF23 effects (Kurosu et al. 2006), and, indeed, initial FGF23-mediated signaling occurs in DCTs (Farrow et al. 2009). However, it remains undetermined how FGF23-mediated signaling in DCTs leads to the regulation of NaPi-IIa and NaPi-IIc in PTCs. It may be possible that FGF23 has a direct action on PTCs (Huang and Moe 2011).

## **4.2.3 Klotho**

Klotho was first identified as an aging suppressor gene product (Kuro-o et al. 1997). It is a single-pass transmembrane protein expressed predominantly in the kidney, intensely in DCTs and to a lesser extent in PTCs and parathyroid gland (Kuro-o 2011). *Klotho*–/– and *Fgf23*–/– mice show very similar phenotypes such as premature aging and abnormal mineral metabolism (Kuro-o 2011). As mentioned above, klotho acts with FGF receptor as a coreceptor in the binding of FGF23 in DCTs for phosphate and vitamin D3 regulation (Kurosu et al. 2006). The Klotho-FGF23-FGF receptor complex in DCTs may produce putative paracrine factors on PTCs where phosphate transporters and enzymes for vitamin D3 regulation are located (Huang and Moe 2011). The extracellular domain of Klotho is also known to be cleaved from plasma membranes, secreted to the circulatoin and present in urine (Hu et al. 2011); this soluble klotho form may directly act on PTCs. Klotho was also found to act as a PTC-synthesized autocrine factor in the FGF23-independent inhibition of NaPi-IIa function by ß-glucuronidase-like enzymatic activity (Hu et al. 2011). Decreased Klotho expression in the kidney may be one of initial factors triggering dysregulation of various hormones involved in phosphate homeostasis and the development of secondary hyperparathyroidism in CKD (Kuro-o 2011).

#### **4.2.4 Vitamin D3**

As mentioned above, megalin and cubilin take up the 25(OH)D3/DBP complex from glomerular filtrates (Nykjaer et al. 1999; Nykjaer et al. 2001; Leheste et al. 2003). In PTCs, 25(OH)D3 is dissociated from DBP and converted by 1α-hydroxylase to the biologically active form 1,25(OH)2D3, which is released to peritubular capillaries. Therefore, dysfunction of these endocytic receptors is an important cause of deficiency of both 25(OH)D3 and

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