*Review* **Klotho**/**FGF23 and Wnt Signaling as ImportantPlayers 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,**‡ **and Mariano Rodriguez 1,2,3,4,**‡


Received: 15 January 2020; Accepted: 11 March 2020; Published: 16 March 2020

**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 augmen<sup>t</sup> phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This e ffect 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 a ffect 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 di fferent 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:** FGFG23; Klotho; Wnt/β-catenin; CKD; cardiorenal syndrome

**Key Contribution:** FGF23, Klotho, and the activation of the Wnt/β-catenin pathway play a critical role in the progression of CKD, but also on di fferent comorbidities associated with CKD such as cardiovascular disease, cardiac fibrosis, bone frailty among others. The interactions between FGF23/Klotho axis and Wnt elements could contribute to pathological processes such as renal hypertension, mineral metabolism alterations, vascular calcification, renal and cardiac fibrosis, cardiac hyperthrophy or arrhythmias.
