Faculty Collaboration Database

FGF23 induces left ventricular hypertrophy. J Clin Invest 2011 Nov;121(11):4393-408

Date

10/12/2011

Pubmed ID

21985788

Pubmed Central ID

PMC3204831

DOI

10.1172/JCI46122

Scopus ID

2-s2.0-80555148939 (requires institutional sign-in at Scopus site)   1632 Citations

Abstract

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Author List

Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M

Author

Joy Lincoln PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Animals
Cohort Studies
Disease Models, Animal
Female
Fibroblast Growth Factor 2
Fibroblast Growth Factors
Glucuronidase
Humans
Hypertrophy, Left Ventricular
Kidney Failure, Chronic
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Models, Cardiovascular
Myocytes, Cardiac
Prospective Studies
Rats
Receptors, Fibroblast Growth Factor
Recombinant Proteins
Signal Transduction
Young Adult