α-Klothoʼs effects on mineral homeostasis are fibroblast growth factor-23 dependent

Abstract

Purpose of reviewα-Klotho (Klotho) occurs in three isoforms, a membrane-bound form acting as a coreceptor for fibroblast growth factor-23 (FGF23) signalling, a shed soluble form consisting of Klotho's large ectodomain thought to act as an enzyme or a hormone, and a secreted truncated form generated by alternative splicing of the Klotho mRNA with unknown function. The purpose of this review is to highlight the recent advances in our understanding of Klotho's function in mineral homeostasis.Recent findingsA number of seminal discoveries have recently been made in this area, shifting existing paradigms. The crystal structure of the ternary FGF receptor (FGFR)-1c/Klotho/FGF23 complex has been uncovered, revealing how the ligand FGF23 interacts with FGFR1c and the coreceptor Klotho at atomic resolution. Furthermore, it was shown that soluble Klotho lacks any glycosidase activity and serves as a bona fide coreceptor for FGF23 signalling. Experiments with a combination of Klotho and Fgf23-deficient mouse models demonstrated that all isoforms of Klotho lack any physiologically relevant, FGF23-independent functions in mineral homeostasis or ageing. Finally, it was demonstrated that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans.SummaryTaken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for mineral homeostasis is their role as coreceptors mediating FGF23 actions. In light of these findings, the main pathophysiological consequence of the downregulation of Klotho observed in acute and chronic renal failure may be the induction of renal FGF23 resistance.

Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25‐Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor‐23

“…( 101,102 ) However, Anour and colleagues ( 103 ) demonstrated that Klotho lacks a vitamin D‐independent physiological role in glucose homeostasis, bone turnover, and steady‐state PTH secretion, in vivo, casting doubt on Klotho alone as a bona fide regulator of any of these phenomena. In a sense, this original research by the Erben group ( 103 ) was prescient and consistent with the recent opinion piece ( 50 ) that “Klotho's effects on mineral homeostasis are fibroblast growth factor‐23 dependent.” Are all Klotho actions dependent upon FGFR1 signal transduction initiated by FGF23? This is the provocative question regarding Klotho in 2020!…”

“…3) via ERK1/2, SGK1, and WNK4 to depress endocytotic removal of TRPV5 from the plasma membrane. ( 50 ) Thus, 1,25(OH) 2 D, by independently inducing TRPV5 ( 82 ) and Klotho, ( 70 ) apparently elicits FGF23‐driven calcium retention at the kidneys. One could speculate, therefore, that 1,25(OH) 2 D/VDR–RXR chronically initiates calcium conservation at the kidneys over a lifetime, possibly to lower the incidence of osteoporosis.…”

“…These transcription factors remain unidentified, although we propose that NRF2 and/or HIF1α are reasonable candidates based on evidence discussed in detail in Section IV.H of this review. Once FGF23 is elaborated by the skeleton, it functions by binding to renal FGFR1c/Klotho co-receptors to promote phosphaturia, (50) calcium reclamation, (51) and repress CYP27B1 (52) as well as induce CYP24A1 (50,53) (Fig. 3), with the latter two actions serving to curb 1,25D levels.…”

“…( 78 ) This circulating Klotho form has been reported to employ the glycosyl hydrolase catalytic activity to regulate the TRPV5 calcium channel ( 79 ) and the renal outer medullary potassium channel 1 (ROMK1). ( 80 ) However, in a recent review, Erben ( 50 ) summarized the work of Chen and colleagues, ( 81 ) who crystallized the ternary complex of the extracellular domain of FGFR1c, FGF23 ligand, and the Klotho ectodomain to provide compelling experimental evidence that Klotho lacks any biologically relevant glycosidase activity. Thus, there has occurred a recent paradigm shift in our understanding of Klotho to reveal that it is devoid of enzymatic activity and instead increases the abundance of TRPV5 on the renal cell membrane through FGF23 signaling (Fig.…”

Protective Role of Vitamin D in Renal Tubulopathies

“…Different pathologic entities that affect renal tubules could be linked to Vitamin D dysregulation. Reaching homeostasis in Vitamin D balance could be a pivotal strategy in the treatment of these diseases [6].…”