In the past 10 years, we have extended our research interest by combining the analysis of pathological signaling events in kidney and heart. We study the Cardiorenal Syndrome with the goal of identifying novel mediators of pathological cardiac remodeling that occurs in the context of chronic kidney disease (CKD). We use a variety of rodent models with primary kidney injury and associated cardiac hypertrophy, induced by surgeries, genetic modifications or changes in the diet. With fibroblast growth factor (FGF) 23 we focus on a circulating factor that is highly elevated in CKD and whose serum levels strongly correlate with cardiac hypertrophy and mortality. Our laboratory was the first to show that FGF23 can directly target cardiac myocytes and induce cardiac hypertrophy in rodents. Our ongoing studies aim to further characterize the cardiac effects of FGF23.
More recently, we have identified FGF receptor isoform 4 (FGFR4) as the cardiac FGF23 receptor, and we could show that an FGFR4-specific blocking antibody reduces cardiac hypertrophy in animal models of CKD. This study may have important clinical implications and suggests that anti-FGFR4 therapy might have cardio-protective effects in CKD. We are also in the process of broadening the focus of our work, and we want to determine whether FGFR4 activation per se is sufficient to induce cardiac remodeling and heart failure in the absence of kidney injury and FGF23 elevations and therefore might serve as a novel drug target for primary cardiomyopathies.
Based on our FGF23-centered studies in the heart, we recently asked the question whether FGF23/FGFR4 signaling also occurs in other tissues, and thereby might contribute to various pathologies associated with CKD and other chronic diseases. Since the liver shows highest FGFR4 expression levels, we established a primary hepatocyte culture system as well as mouse models with hepatocyte-specific genetic modifications and injury in order to study potential hepatic effects of FGF23/FGFR4. We found that FGF23 can directly target hepatocytes via FGFR4 and induce the expression of inflammatory cytokines and regulators of iron metabolism and thereby might contribute to systemic inflammation and anemia. Furthermore, in collaboration with outside investigators, we found that FGF23/FGFR4 drives local inflammation in various lung disease, and that FGFR4 signaling contributes to altered T cell response in cancer. These studies suggest that pharmacologic FGFR4 blockade might have a broad therapeutic value.
We are also interested in studying the crosstalk between FGF23, active vitamin D (1,25D) and soluble klotho (sKL), and how these three factors communicate with each other on a molecular, cellular and physiological level. We postulate that 1,25D and sKL inhibit the pathologic actions of FGF23 on the heart and liver. Since current tools to detect sKL in rodents or humans are not reliable and commercially available sKL proteins seem to lack sufficient bioactivity, we focus on establishing a novel assay to detect sKL in serum, urine and cell culture supernatants in a specific and quantitative manner, and we have designed a synthesis and purification approach to produce recombinant sKL protein that has high stability and bioactivity.
Since in CKD elevations of serum FGF23 levels go hand in hand with high phosphate concentrations, we recently started to study the direct effects of inorganic phosphate on cardiac myocytes and hepatocytes, with the goal to determine whether hyperphosphatemia contributes to pathologic cardiac remodeling, systemic inflammation and anemia in the context of CKD. CKD is a pathologic state that shows various features of accelerated aging. Therefore, we postulate that the crosstalk between FGF23 and sKL driving distant organ damage caused by primary kidney injury, also contributes to pathologies ithat occur n the normal aging process, such as cardiovascular injury. Therefore, we aim to transfer our mechanistic findings from animal models of CKD to models of aging.
CKD is a pathologic state that shows various features of accelerated aging. Therefore, we postulate that the crosstalk between FGF23 and sKL driving distant organ damage caused by primary kidney injury as well as high phosphate levels, also contribute to pathologies that occur in the normal aging process, such as cardiovascular injury. Therefore, we aim to transfer our mechanistic findings from animal models of CKD to models of aging.