*2.9. Klotho*

Membrane-bound Klotho serves as a co-receptor for FGF23 signaling and is synthesized in the kidney and bone. Soluble Klotho shows endocrine actions correlated with anti-aging e ffects [65]. Soluble Klotho levels are decreased in CKD [65]. Using Klotho-deficient mice, it could be shown that the Klotho-FGF23 axis plays a key role in pathologic cardiac remodeling in CKD, but also in phosphotoxicity and aging [66]. In pediatric CKD patients, serum FGF23 levels increased and Klotho levels decreased with progressing renal failure, while phosphorus levels were maintained in the normal range [67]. In those patients, high FGF23 and low Klotho levels were strongly associated with impaired left ventricular diastolic function [67]. In addition to this finding, FGF23 signaling via fibroblast growth factor receptor 4 (FGFR4) activates the phospholipase C γ/calcineurin/nuclear factor of the activated T-cell pathway, and thus promotes cardiac myocyte hypertrophy, independent of its co-receptor Klotho [60,67]. Furthermore, FGFR4 signaling is responsible for FGF23-mediated increased cardiac contractility [68]. Correspondingly, aging mice lacking FGFR4 were protected from LVH. Thus, FGF23/FGFR4 signaling plays an important role in the regulation of cardiac remodeling and function [68]. Additionally, pharmacological blockade of the FGF receptor improved cardiac structure and function in 5/6 nephrectomy rats, thus underlining the role of FGFR activation as a mechanism of LVH in CKD [59].
