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.
Highlights
Chronic kidney disease (CKD) causes alterations in mineral metabolism, which worsens as the renal disease progresses
These results suggest that the increased phosphate medium produced nuclear translocation of β-catenin that was followed by a reduction in tubular load of phosphate causes a reduction in Klotho expression
The upregulation of Klotho halts the activation of Wnt, which reduces the deposition of the extracellular matrix and decreases the transcription of cytokines [32]
Summary
Chronic kidney disease (CKD) causes alterations in mineral metabolism, which worsens as the renal disease progresses. There are studies showing the pleiotropic effects of Klotho in the cardiovascular system [2], bone [3], and even as a tumor suppressor molecule [4,5] The mechanisms behind this reduction of renal α-Klotho during CKD are unclear, and they are attributed mainly to kidney function deterioration, Wnt/β-catenin activation has been suggested as a key factor leading to Klotho reduction [6]. It is interesting to note that in parallel to the decrease of Klotho, and the increase of FGF23, there are changes in the levels of Wnt inhibitors, such as sclerostin or Dickkopf-related proteins (Dkk). The canonical Wnt pathway involves the nuclear translocation of β-catenin and the activation of the target genes via TCF/LEF transcription factors (Figure 1).
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