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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 Article has an altmetric score of 31

FGF23 induces left ventricular hypertrophy

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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 3

FGF23 and FGF2 use different signaling pathways to induce hypertrophy of NRVMs.

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FGF23 and FGF2 use different signaling pathways to induce hypertrophy of...
(A) Klotho expression is detectable in mouse brain (Br) and kidney (K) by nested RT-PCR but not in heart (H), isolated cardiomyocytes (CM), or in the absence of template (blank [Bl]). (B) FGFR1–FGFR4 are detectable in liver (L), heart, and isolated cardiomyocytes by RT-PCR but not in the absence of template. (C) Surface area of isolated NRVMs after 48 hours of FGF treatment alone and in the presence of inhibitors. The lower edge of the bars represents the mean (± SEM) area, and their height represents the difference in area compared with that of cells that were treated with FGF alone (red). Inhibiting FGFR (gray) prevents any increase in area regardless of FGF concentration. ERK inhibition (orange shades) completely prevents FGF2-induced hypertrophy but only partially prevents FGF23-induced hypertrophy. PI3K/Akt inhibition (green shades) partially prevents FGF2-induced hypertrophy but has no effect on FGF23-treated cells. PLCγ/calcineurin inhibition (blue shades) prevents FGF23-induced hypertrophy but not FGF2-induced hypertrophy (150 cells per condition; *P < 0.01, compared with corresponding FGF concentration without inhibitor). (D) FGF2 stimulates a greater increase in ERK phosphorylation (p-ERK) and Egr-1 expression than FGF23 relative to total ERK (t-ERK). (E) FGF23 but not FGF2 increases NFAT activity in C2C12 myoblasts. Cyclosporine A (CsA) blocks the effect of FGF23 (values represent fold change ± SEM compared with vehicle; *P < 0.01, compared with vehicle). (F) Only FGF2 induces an increase in Akt phosphorylation (p-Akt) relative to total Akt (t-Akt).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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