FGF23 induces left ventricular hypertrophy
Christian Faul, … , Martin G. Keane, Myles Wolf
Christian Faul, … , Martin G. Keane, Myles Wolf
Published October 10, 2011
Citation Information: J Clin Invest. 2011;121(11):4393-4408. https://doi.org/10.1172/JCI46122.
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Research Article Nephrology

FGF23 induces left ventricular hypertrophy

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.

Authors

Christian Faul, Ansel P. Amaral, Behzad Oskouei, Ming-Chang Hu, Alexis Sloan, Tamara Isakova, Orlando M. Gutiérrez, Robier Aguillon-Prada, Joy Lincoln, Joshua M. Hare, Peter Mundel, Azorides Morales, Julia Scialla, Michael Fischer, Elsayed Z. Soliman, Jing Chen, Alan S. Go, Sylvia E. Rosas, Lisa Nessel, Raymond R. Townsend, Harold I. Feldman, Martin St. John Sutton, Akinlolu Ojo, Crystal Gadegbeku, Giovana Seno Di Marco, Stefan Reuter, Dominik Kentrup, Klaus Tiemann, Marcus Brand, Joseph A. Hill, Orson W. Moe, Makoto Kuro-o, John W. Kusek, Martin G. Keane, Myles Wolf

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Figure 2

FGF23 increases the surface area of isolated NRVMs and activates hypertrophic gene programs.

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FGF23 increases the surface area of isolated NRVMs and activates hypertr...
(A) Surface area of isolated NRVMs increases after FGF23 and FGF2 treatment, as revealed by immunocytochemical analysis using antibodies to α-actinin (red). DAPI (blue) identifies nuclei (original magnification, ×100; scale bar: 25 μm). (B) Compared with that of untreated control cells (white), 48 hours of treatment with FGF23 (blue) or FGF2 (red) significantly increases cell surface area (mean ± SEM). Fifty cells per group per isolation were analyzed by morphometry (n = 3 isolations of NRVMs; *P < 0.01, compared with untreated). (C) Compared with those of untreated control cells (white), FGF23 (blue) or FGF2 (red) significantly increase α-actinin protein levels normalized to GAPDH in isolated NRVMs, as determined by immunoblotting (mean ± SEM; n = 3 isolations of NRVMs; *P < 0.01). (D) Compared with that of untreated control cells (white), FGF23 (blue) or FGF2 (red) decrease expression of α-MHC and MCAD mRNA and increase β-MHC, ANP, and BNP) mRNA (mean ± SEM; n = 3 isolations of NRVMs quantified by RT-PCR normalized to Gapdh; *P < 0.01, compared with untreated).