*4.1. Klotho, Wnt*/β*-Catenin, and RAS*

Another point of interest is the association between Wnt/β-catenin signaling and the Pro-Renin Receptor (PRR), a component of the RAS, and critical regulator of blood pressure [42]. In the kidney, PRR is involved in nephron formation, podocytes instability, blood pressure regulation, and sodium transport [42,43]. PRR increases as CKD progress; however, the mechanisms leading are not fully understood. A recent study has demonstrated that Wnt/β-catenin stimulates PRR mRNA expression of in a dose-dependent manner [42]. Similarly, PRR overexpression triggers Wnt gene transcription, perpetuating a cycle that exacerbates kidney fibrosis and a decline of renal function. Multiple RAS genes are direct targets of Wnt/β-catenin signaling [44].

However, to date, there is no evidence showing the relationship between Klotho reduction and PRR expression. Given that CKD and Wnt/β-catenin signaling regulate PRR expression, and FGF23 enhances sodium reabsorption through sodium/chloride cotransporter in the distal tubule [45,46], it can be hypothesized that increased FGF23, Wnt activation, and the downregulation of Klotho in CKD may promote volume overload and an elevation in blood pressure, two well-known risk factors for heart failure. Nevertheless, this remains speculative and requires further investigation. Therefore, FGF23, Klotho, and the Wnt pathway may have relevance in the control of blood pressure and RAS.
