Effects of soluble Klotho and active vitamin D on FGF23-induced cardiac hypertrophy

• Applicant: Dr. Beatrice Richter
• Subject Area: Nephrology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398311091

The hormone fibroblast growth factor (FGF) 23 is produced in the bone and regulates the excretion of phosphate in the kidney as well as serum levels of active vitamin D (also termed 1,25D or calcitriol). To do so, FGF23 binds to the FGF receptor (FGFR)-Klotho complex. Four different FGFR isoforms have been described and the membrane-bound protein Klotho serves as a co-receptor for FGF23 to support FGFR binding. Klotho also exists as a soluble form that can be detected in the blood. When the kidney function declines during the progression of chronic kidney disease (CKD), rising serum phosphate levels induce an increase in FGF23 production. CKD is characterized by up to 1000-fold enhanced FGF23 levels, decreased serum levels of soluble Klotho and reduced 1,25D. In CKD patients, these alterations are associated with an increased risk of developing cardiovascular disease, including cardiac hypertrophy, as well as increased mortality. In pevious mechanistic studies we have found that FGF23 can bind FGFR4 on cardiomyocytes and thereby activate an intracellular pro-hypertrophic signaling cascade mediated by PLCγ/calcineurin/NFAT. The hypothesis of this study is that soluble Klotho and/or 1,25D inhibit FGF23-induced cardiac hypertrophie. We will investigate, if soluble Klotho can bind FGF23 and/or FGFR4 and either block the pro-hypertrophic cascade or induce a different signaling pathway in cardiomyocytes. In terms of 1,25D, we will study, if its binding to the vitamin D receptor directly prevents the activation of the FGFR4-linked protein PLCγ thereby blocking the cascade resulting in cardiac hypertrophy. If successful, our results could serve as the base for a novel, more efficient therapeutic strategy for the treatment of patients with CKD, including a combination of decreasing or blocking FGF23 and increasing serum levels of soluble Klotho and vitamin D.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Christian Faul