Postdoc Fellowship for Guillaume Courbon: Cardiorenal effects of iron and phosphate in chronic kidney disease: role of fibroblast growth factor 23

Project: Research project

Project Details

Description

Chronic Kidney Disease (CKD) affects over 20 million adults in the US alone. CKD poses an enormous $58 billion annual burden on the US health system, and cardiovascular disease (CVD) is a major driver of these trends: CVD events are more common and CVD outcomes far worse in patients with CKD than in the general population. These observations support the need to design novel therapeutic strategies to prevent CKD progression and excess CVD, but the mechanisms are poorly understood. Elevated levels of the phosphate regulating hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful risk factor and novel mechanism of CKD progression, CVD events and death. Hyperphosphatemia and iron deficiency, two common complications of CKD are associated with CKD progression and CVD and are also potent stimuli of FGF23 production. Collectively, these data suggest that elevated FGF23 may be a novel therapeutic target for attenuating renal and heart failure, and consequently, reducing FGF23 levels will selectively attenuate the renal and cardiac toxicity of FGF23. However, the interplay between phosphate, iron and FGF23 has not been studied in the context of CKD, and specific mechanisms have not been identified. In this application, we propose to study the individual and combined effects of targeting phosphate, iron and FGF23 in CKD, to prevent renal and cardiac injury in a mouse model of CKD. In the first aim, our primary goal is to demonstrate the combined benefits of dietary iron supplementation and phosphate restriction in the prevention of renal and cardiac dysfunction during the development of CKD. We propose to study the effects of phosphate and iron based therapies in the Col4a3KO mouse model of progressive CKD, and assess the renal and cardiac effects in mice fed either low-phosphate, high iron and combined low-phosphate/high iron diets. Since lowering phosphate and/or increasing iron will result in FGF23 reductions, in the second aim, our goal is to define the FGF23-dependent and independent effects of phosphate and iron therapies. We first propose to study Col4a3KO-FGF23cKO mice harboring a bone specific deletion of FGF23, which will display lower levels of FGF23, a similar disordered iron metabolism and similar to higher levels of phosphate compared to Col4a3KO mice. We next propose to feed WT, FGF23cKO, Col4a3KO and Col4a3KO-FGF23cKO mice either low-phosphate or high iron diets to individually correct hyperphosphatemia and iron deficiency and further assess the impact on the cardiorenal phenotype, in absence of FGF23 excess. Exciting preliminary data support our innovative hypotheses, and all animal models are already established and available in our laboratory. Most importantly, our studies will define novel therapeutic targets for preventing or treating renal and heart failure.
StatusActive
Effective start/end date1/1/1912/31/20

Funding

  • American Heart Association (19POST34380583)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.