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 6

Klotho-deficient and klotho heterozygous mice develop LVH.

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Klotho-deficient and klotho heterozygous mice develop LVH. (A) kl/kl mic...
(A) kl/kl mice demonstrate significant increases in serum levels of FGF23, phosphate, and 1,25-dihydroxyvitamin D compared with those of wild-type mice. Only FGF23 was significantly increased in kl/+ mice. (B) Representative gross pathology of sagittal and mid-chamber sections of the heart (hematoxylin and eosin stain; original magnification, ×5; scale bar: 200 μm) and WGA-stained sections from the left ventricular mid-chamber free wall (original magnification, ×63; scale bar: 50 μm) demonstrate LVH in kl/kl and kl/+ mice. (C) kl/kl and kl/+ mice manifest significant increases in left ventricular wall thickness. (D) kl/kl and kl/+ mice manifest significant increases in the ratio of heart weight to total body weight. (E) kl/kl and kl/+ mice manifest significant increases in left ventricular relative wall thickness. (F) kl/kl and kl/+ mice manifest significant increases in cross-sectional surface area of individual cardiomyocytes. (G) kl/kl and kl/+ mice demonstrate decreased levels of α-MHC and MCAD mRNA and increased β-MHC, ANP, and BNP mRNA. All values are mean ± SEM (n = 6 mice per group for all laboratory and morphological analyses; n = 3 mice per group for RT-PCR analyses; n = 100 cells per group for WGA analysis; *P < 0.01, compared with WT; **P < 0.01, compared with kl/+).