Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

Abstract

Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins- βKlotho and γKlotho; only αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH, and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+dependent phosphate cotransporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.

Role of sodium‐dependent Pi transporter/Npt2c on Pi homeostasis in klotho knockout mice different properties between juvenile and adult stages

“…These phenotypes were also observed in kl/kl mice, but both Npt2a and Npt2c were increased in the kl/kl mice. The KLKO mouse phenotypes were similar to those described in several previous studies (Alexander et al, ; Hu et al, , ; Kuro‐o et al, ; Morishita et al, ; Ohnishi et al, ; Ohnishi, Nakatani, Lanske, & Razzaque, ; Segawa et al, ; Tsujikawa et al, ; Yoshida et al, ).…”

“…These findings suggest that kl/kl mice are not suitable for examining the effects of dietary Pi. α-Klotho knockout (KLKO) mice have a phenotype similar to that of kl/kl mice (Alexander et al, 2009;Hu et al, 2019Hu et al, , 2011Kuro-o et al, 1997;Morishita et al, 2001;Ohnishi, Nakatani, Lanske, & Razzaque, 2009a, 2009bSegawa et al, 2007;Tsujikawa, Kurotaki, Fujimori, Fukuda, & Nabeshima, 2003;Yoshida, Fujimori, & Nabeshima, 2002). A detailed analysis of Pi metabolism in KLKO mice has not yet been reported.…”

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

“…The current manuscript provides new data linking autophagy with phosphate transport in the renal tubules. Autophagy might modulate NaPi2a/2c endocytosis via the canonical mechanisms of modification of trafficking [73][74][75][76] to control renal tubular Pi reabsorption. Alternatively, there can be novel mechanisms by which autophagy can regulated NaPi protein distribution and activity.…”

Endothelin receptor B controls the production of fibroblast growth factor 23

“…Fibroblast growth factor 23 (FGF23) is a protein with endocrine and paracrine effects . It is mainly synthesized by bone cells, but also other cells including immune cells and cardiomyocytes produce it .…”

“…It is mainly synthesized by bone cells, but also other cells including immune cells and cardiomyocytes produce it . FGF23 mainly exerts its endocrine effects in the kidney where it inhibits phosphate reabsorption by down‐regulating phosphate transporter NaP i IIa ( SLC34A1 ) and the production of 1,25(OH) 2 D 3 , the active form of vitamin D . Moreover, it inhibits the secretion of parathyroid hormone (PTH) and regulates renal Ca 2+ absorption .…”