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Review
. 2020 Mar 16;12(3):185.
doi: 10.3390/toxins12030185.

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease

Juan Rafael Muñoz-Castañeda  1   2   3   4 , Cristian Rodelo-Haad  1   2   3   4 , Maria Victoria Pendon-Ruiz de Mier  1   2   3   4 , Alejandro Martin-Malo  1   2   3   4 , Rafael Santamaria  1   2   3   4 , Mariano Rodriguez  1   2   3   4
Affiliations
Review

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease

Juan Rafael Muñoz-Castañeda et al. Toxins (Basel). .

Abstract

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications.

Keywords: CKD; FGFG23; Klotho; Wnt/β-catenin; cardiorenal syndrome.

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Conflict of interest statement

M.R. has received honorarium for lectures from Abbott, Amgen, Inc., Fresenius, and Shire. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Simplified scheme of the Wnt/β-catenin signaling pathway. (A) Wnt ligand interaction with Frizzled protein and LRP5/6. Disheveled (DVL) protein binds the Frizzled receptor and sequester the protein complex CK1a-GSK3-Axin-APC blocking β-catenin phosphorylation and degradation. β-catenin activates TCF/LEF transcription factor in the nucleus. (B) Interference of Wnt ligand–Frizzled protein interaction by sFRP, SOST, or DKK1. Disheveled (DVL) protein does not bind to the Frizzled receptor. Protein complex GSK3-Axin-APC phosphorylates β-catenin. Phosphorylated β-catenin is led to proteasomal degradation. Abbreviations: GSK3β: glycogen synthase kinase 3; APC: adenomatous polyposis coli; TCF/LEF: T-cell factor/lymphoid enhancer-binding factor; sFRP: secreted Frizzled-related proteins; SOST: sclerostin; DKK1: Dickkopf-related proteins.
Figure 2
Figure 2
Schematic representation of FGF23/Klotho interactions with the Wnt/β-catenin pathway in the bone, kidney, and heart.
See this image and copyright information in PMC

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