GAT FGF23 and Vascular Calcification

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 DESCRIPTION (provided by applicant): FGF23 and Vascular Calcification ABSTRACT Patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) have a shortened life span and cardiovascular disease is the leading cause of death in these patients. Vascular calcification is highly prevalent in patients with CKD and ESRD, is noted to occur at an early age, and is a strong predictor of cardiovascular outcome. Risk factors for vascular calcification include hyperphosphatemia, uremia and increased calcium phosphate product but patients with CKD develop vascular calcification prior to the development of these overt biochemical abnormalities. Recent clinical studies have demonstrated an association between vascular calcification and elevated fibroblast growth factor 23 (FGF23) levels in patients with CKD/ESRD. To study the role of FGF23 in vascular calcification in vivo has been fraught with problems until now. An ideal in vivo model would be an animal model with no major disturbances in serum phosphate levels, serum calcium levels or renal function but have elevated FGF23 levels so that the independent effects of FGF23 on vascular calcification can be studied. We have now developed such an ideal mouse model; Fgfr1-/-/Fgfr4-/- mice. This model involves a kidney conditional deletion of fibroblast growth factor receptor 1 (Fgfr1) and a global deletion of fibroblast growth factor receptor 4 (Fgfr4). Fgfr1-/-/Fgfr4-/- mice have ~50 fol elevated FGF23 levels, normal renal function and serum calcium levels and lack hypophosphatemia. Fgfr4 is not normally expressed in mouse aorta, the subject of vascular calcification in our study. Therefore, global deletion of Fgfr4 in our Fgfr1-/-/Fgfr4-/- mice will have no effect on studying the effects of FGF23 on aortic calcification. We plan to study the role of FGF23 in vascular calcification using wild type and Fgfr1-/-/Fgfr4-/- mice in states of hyperphosphatemia or uremia. We are able to achieve desired and comparable serum phosphorus levels while maintaining normal renal function in both groups of mice with dietary alteration alone. Additionally, to understand the role of uremic toxins and FGF23 together on vascular calcification, we will induce a CKD state with dietary adenine. If the proposed experiments in this grant confirm our hypothesis, this work would have a great impact on defining the independent role of FGF23 on the vasculature and the associated cardiovascular morbidity and mortality in patients with CKD/ESRD. Ultimately, understanding the role of FGF23 in vascular calcification will allow for targeted therapy to ameliorate this process which in turn will have a huge impact on improving survival of patients with CKD/ESRD.