This is an F30 application to study the effects of fibroblast growth factor 23 (FGF23) on podocytes by Ansel Amaral, an MD/PhD student at the University of Miami. The PI was a previous recipient of the NIH Physician Scientist Training Program award (1R25DK059644-01) and is already actively involved in the laboratory's translational research program, marked by one recently submitted first author publication. Sponsor and Environment: The primary sponsor, Peter Mundel, is an international expert in podocyte biology. He has been continuously funded by NIH since 2001 and has an extensive track record of laboratory mentorship. The Co-Sponsor, Myles Wolf, is an international expert in FGF23 research and also an NIH funded investigator with an extensive track record of mentorship. Christian Faul, another Co-Sponsor, is an expert in podocyte cell signaling. The PI has access to a rich environment for scientific development led by his Sponsors'complementary expertise in the areas of FGF23, podocyte biology, and clinical research. Proposal: Chronic kidney disease (CKD) is a growing worldwide public health concern. Over 11% of adults living in the US are estimated to suffer from CKD, which leads to a diminished quality of life, financial health burden and premature death. Disordered phosphorus metabolism is one of the most common complications that contribute to decreased lifespan in CKD. An early manifestation of disordered phosphorus metabolism in CKD is increased secretion of FGF23 by osteocytes. FGF23 is a recently discovered endocrine hormone that increases urinary phosphate excretion and inhibits renal calcitriol production. Through these effects, FGF23 helps maintain normal serum phosphate levels in CKD patients despite progressive reduction in the renal capacity to excrete phosphate. Recent data from the Co-Sponsor demonstrated that increased FGF23 levels in CKD patients are independently associated with progression of CKD, cardiovascular disease and death. Whether direct effects of FGF23 mediate these findings has not yet been studied in detail. The purpose of this proposal is to test the hypothesis that FGF23 exerts direct effects on renal podocytes, which have been implicated as the target cells of several patterns of renal injury in innovative work performed by the Sponsor's laboratory. Our preliminary data indicate that cultured podocytes respond to FGF23 by displaying changes in the dynamics of the actin cytoskeleton and undergoing hypertrophic cell growth. We plan to extend these in vitro experiments and propose novel in vivo models to further characterize the pathological effects of FGF23 on podocyte morphology and function. We hypothesize that FGF23 excess initially induces reversible changes such as podocyte foot process effacement and hypertrophy, followed by irreversible injury leading to podocyte loss and eventually to total nephron and overall kidney damage. Given that FGF23 levels rise beginning in early CKD, the results would highlight FGF23 and its downstream signaling pathways in podocytes as a novel target for clinical intervention aimed at reducing the burden of CKD and its associated complications.

Public Health Relevance

Chronic kidney disease (CKD) affects over 11% of the US population, is disproportionately elevated in minority populations and those of lower economic status, and accounts for nearly $60 billion in healthcare spending, nearly 30% of the annual Medicare budget. Substantial clinical evidence has indicated that serum fibroblast growth factor 23 (FGF23) levels rise early in the course of CKD and are independently associated with mortality in patients suffering from CKD;however, so far FGF23 has only been considered as a potential biomarker for CKD, rather than a molecular factor that can directly cause the disease. This research endeavors to determine the direct pathological effects of FGF23 on podocytes and on the glomerular filter function of the kidney, with the eventual aim of revealing a novel therapeutic target for CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK091057-04
Application #
8538953
Study Section
Special Emphasis Panel (ZDK1-GRB-G (O1))
Program Officer
Rankin, Tracy L
Project Start
2010-09-30
Project End
2016-09-29
Budget Start
2013-09-30
Budget End
2014-09-29
Support Year
4
Fiscal Year
2013
Total Cost
$47,232
Indirect Cost
Name
University of Miami School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Faul, Christian; Amaral, Ansel P; Oskouei, Behzad et al. (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393-408