*2.7. Growth Factors*

In addition to the above-mentioned metabolic and inflammatory pathways, several growth factors might play important roles in cardiac fibrosis in CKD. One of the profibrotic modulators that stimulates fibroblast proliferation is FGF2. FGF2 binds to FGF-receptor (FGFR) 1, which is expressed in human cardiomyocytes. Additionally, FGF2 has been shown to promote growth of isolated cardiomyocytes [47,48] and cardiac hypertrophy in rats following myocardial infarction [49], thus further contributing to the cardiac phenotype in the cardiorenal syndrome. Another important growth factor-based mechanism of cardiac fibrosis development was found by analyzing human heart specimens. A marked reduction in cardiac Klotho, often found in CKD patients, was associated with increased TGF-β signaling. This in turn upregulated Wnt signaling, a major pathway in fibrosis. This was confirmed by in vitro studies with cardiomyocytes, where upregulation of endogenous Klotho inhibited Wnt/β-catenin signaling [50].
