*4.3. FGF23–Klotho–Wnt and Cardiac Fibrosis*

During cardiac fibrosis some of the evidences showing a crosstalk of FGF23 and Klotho with Wnt signaling are described. Cardiac fibrosis is characterized as an excessive accumulation of fibroblasts, myofibroblasts, and extracellular matrix proteins in the myocardium [54]. Human hearts with severe epicardial fibrosis show increased activation of β-catenin and TCF/LEF [55]. Additionally, TGF-β is a key profibrotic cytokine in the development of cardiac fibrogenesis. It has been proposed that TGF-β activates Wnt/β-catenin signaling through the production of Wnt proteins, and by direct deactivation of GSK3β. Activated Wnt/β-catenin, in turn, stabilizes the TGF-β/Smad response. It appears that the co-activation of these two pathways is required to trigger the e ffective fibrotic response [56]. Akhmetshina et al. showed that canonical Wnt signaling activation is required for TGF-β-mediated fibrosis [57]. Recently, Liu Q et al. showed through in vitro studies that the loss of endogenous cardiac Klotho in CKD patients, specifically in cardiomyocytes, intensifies TGF-β1 signaling, which enables more vigorous cardiac fibrosis through upregulation of Wnt signaling. Moreover, the upregulation of endogenous Klotho inhibited Wnt/β-catenin signaling [58], a desirable strategy for the prevention and treatment of cardiac fibrosis in CKD patients.

Other authors have shown that secreted Klotho can inhibit TGF-β1 signaling through its interaction with TGF-β1 cell-surface receptors [59].

With respect to FGF23, Hao et al. observed that in cultured adult mouse cardiac fibroblasts, rFGF23 increased active β-catenin, procollagen I, and procollagen III expression [60]. Schumacher et al. showed that FGF23 increased the expression of Collagen 1, MMP8, and fibronectin in cardiac fibroblasts; in addition, they showed that high levels of FGF23 increased the expression of TGF-β1 in M2 polarized macrophages [61]. So, FGF23 might be involved also in cardiac fibrosis generation.

These studies reveal a close association between Klotho, TGF-β, and Wnt signaling activation in the generation of cardiac fibrosis. The evaluation of these parameters in the context of clinical studies will determine if modulation of Wnt signaling could be a potential therapeutic target.
