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

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.

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

“…Studies have revealed the pleiotropic effect of klotho on bone, the cardiovascular system, and even as a tumour-suppressor molecule [187,234]. Some researchers suggest that (sKL) binds to multiple Wnt ligands, suppressing various gene transcriptions.…”

“…Some researchers suggest that (sKL) binds to multiple Wnt ligands, suppressing various gene transcriptions. Increasing klotho regulation stops Wnt activation, which reduces extracellular matrix deposition and cytokine transcription [234]. It seems that klotho deficiency may contribute to the cardiac hypertrophy observed in CKD (stages G3a-b and G4).…”

New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis

“…The expression of renal Klotho is decreasing with the progression of kidney injury, where the amount of functional nephrons are reduced and the transfer of phosphate per nephron increased [132]. Interestingly, it has been suggested that the expression of renal Klotho was modulated by phosphaturia and that inhibition of Wnt/ β-catenin signaling prevented the phosphate induced downregulation of Klotho [133,134] Recently, we have examined such a new paradigm and its potential impact on CKD-MBD. We used the unilateral nephrectomy model (UUO), which is ideal to study the rapid development of unilateral renal fibrosis (characterized by induced periostin, decrease BMP7 and Klotho expression) in a non-uremic milieu as the contralateral kidney maintains a normal glomerular filtration [104].…”

Editorial on the Special Issue “Comorbidities in Chronic Kidney Disease”

“…Muñoz-Castañeda et al [ 33 ] further elaborate on the FGF23–Klotho axis, its regulation by the Wnt/β-catenin signaling pathway and vice versa. Starting from their deregulation in CKD, the impact of these axes on pathophysiological processes underlying CKD progression as well as cardiovascular disease and bone disorders are being discussed in detail.…”