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 1

Elevated circulating FGF23 levels are associated with LVH in patients with CKD.

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Elevated circulating FGF23 levels are associated with LVH in patients wi...
(A) The distribution of FGF23 levels in baseline samples of 3,070 participants who enrolled in the CRIC study and underwent echocardiography 1 year later. The median FGF23 was 142 RU/ml. Fifty-eight participants with FGF23 of more than 1,000 RU/ml (range 1,054–14,319 RU/ml), who were included in the analysis, are not shown here. (B) Ascending quartiles of FGF23 were associated with significantly decreased ejection fraction (P for linear trend < 0.001), but the differences between groups were modest, and the mean (± SEM) ejection fraction for each quartile was normal (>50%). (C) Ascending quartiles of FGF23 were associated with significantly increased mean (± SEM) left ventricular mass index (P for linear trend < 0.001). (D) With increasing quartiles of FGF23, the prevalence of concentric (gray) and eccentric (green) LVH increased at the expense of normal left ventricular geometry (white) and left ventricular remodeling (blue) (P < 0.001). Numbers in the bars represent the percentages of prevalence for each condition.