Role of Fibroblast Growth Factor-23 (FGF-23) in the Anemia of Cardiovascular Disease
Abstract
The Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area under which this application is submitted is Cardiovascular Health. Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), with a mortality rate 20-30 times higher than that of individuals with normal kidney function. Severe anemia is a common complication in both CVD and CKD, and it is associated with increased mortality in patients with heart failure and adverse long-term outcomes in the presence of CKD. Anemia affects more than 80% of CVD and CKD patients, and it is mainly caused by markedly reduced capacity of the patients diseased kidneys to produce erythropoietin (Epo), the hormone that stimulates the bone marrow (BM) to produce red blood cells (RBCs). We have recently published that high Fibroblast Growth Factor-23 (FGF-23) levels are associated with decreased erythropoiesis, the process of RBC production. Conversely, loss of Fgf-23 results in increased erythropoiesis. These novel findings have major clinical implications. FGF-23 is a bone-secreted hormone that acts on the kidney and it is widely recognized as the most important regulator of phosphate and vitamin D homeostasis and bone mineralization. Circulating FGF-23 levels rise dramatically in CKD patients as renal function declines, and they have been linked to greater cardiovascular risk, higher vascular and aortic calcifications, cardiac hypertrophy, and mortality. CKD-associated anemia is currently treated with injections of synthetic Epo. However, Epo treatment is not only expensive, but epidemiological studies indicate that a number of patients receiving Epo develop thrombosis, hypertension, tumor growth, as well as resistance to Epo therapy itself. Therefore, there is a need to discover mechanisms that would stimulate RBC production independently of Epo and have fewer side effects. The objective of the proposed study is to unravel the role that FGF-23 plays in the anemia associated with renal and cardiovascular disease. Our hypothesis is that FGF-23 impairs erythropoiesis by mechanisms that are mediated by Epo as well as mechanisms that are independent of Epo and that inhibiting FGF-23 activity can restore erythropoiesis and correct anemia. In the proposed studies, we will (a) evaluate the effect of inhibiting FGF-23 activity in the anemia associated with renal failure and (b) determine the molecular mechanism(s) of FGF-23 action on erythropoiesis. Our findings will open new avenues in the treatment of blood disorders such as anemia by blocking FGF-23 action as a targeted therapy. Our study is the first to evaluate FGF-23 as a causative factor in the development of common anemia, and it will determine if inhibiting FGF-23 activity can be used as a targeted therapy for the correction of anemia (e.g., in CVD and CKD). This research proposal has enormous clinical significance as it addresses a crucial health problem, and the data generated will have important impact in the treatment of a severe common disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610598
Entities
People
- Despina Sitara
Organizations
- New York University
- United States Army