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FGF23 induces left ventricular hypertrophy
Open accessAbstract
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.
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“Data from animal studies and healthy subjects indicate that longer treatment with high Pi can lead to cardiac remodeling in animals and higher blood pressure in humans [19, 35, 42].”
From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [19]
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Metadata
- Authors
- Faul, C., Amaral, A. P., Oskouei, B., Hu, M.-C., Sloan, A., Isakova, T., Gutiérrez, O. M., Aguillon-Prada, R., Lincoln, J., Hare, J. M., Mundel, P., Morales, A., Scialla, J., Fischer, M., Soliman, E. Z., Chen, J., Go, A. S., Rosas, S. E., Nessel, L., Townsend, R. R., Feldman, H. I., St. John Sutton, M., Ojo, A., Gadegbeku, C., Di Marco, G. S., Reuter, S., Kentrup, D., Tiemann, K., Brand, M., Hill, J. A., Moe, O. W., Kuro-o, M., Kusek, J. W., Keane, M. G., & Wolf, M.
- Affiliations
- University of Miami (US)
- The University of Texas Southwestern Medical Center (US)
- University of Alabama at Birmingham (US)
- Harvard University (US)
- University of Illinois Chicago (US)
- Wake Forest University (US)
- Tulane University (US)
- University of California, San Francisco (US)
- University of Pennsylvania (US)
- University of Michigan (US)
- Temple University (US)
- University of Münster (DE)
- National Institutes of Health (US)
- ORCID
- Faul, Christian
- Amaral, Ansel P.
- Isakova, Tamara
- Gutiérrez, Orlando M.
- Lincoln, Joy
- Hare, Joshua M.
- Mundel, Peter
- Scialla, Julia
- Fischer, Michael
- Soliman, Elsayed Z.
- Chen, Jing
- Go, Alan S.
- Rosas, Sylvia E.
- Townsend, Raymond R.
- Feldman, Harold I.
- Ojo, Akinlolu
- Reuter, Stefan
- Kentrup, Dominik
- Tiemann, Klaus
- Hill, Joseph A.
- Moe, Orson W.
- Keane, Martin G.
- Wolf, Myles
- Venue
- Journal of Clinical Investigation
- Published
- 2011-11-01
- Volume
- 121
- Issue
- 11
- Pages
- 4393-4408
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3204831
- OpenAlex
- W2015668150
- Cited by
- 2,027
- References
- 92
- Citations by year
- 2026: 83 · 2025: 92 · 2024: 81 · 2023: 124 · 2022: 135 · 2021: 172 · 2020: 126 · 2019: 144 · 2018: 175 · 2017: 152 · 2016: 154 · 2015: 152 · 2014: 170 · 2013: 155 · 2012: 104
- FWCI
- 107.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- Abbott Laboratories
- Amgen
- Nephcure Foundation
- University of Miami
- University of Pennsylvania
- Health Services Research and Development
- Cleveland Clinic
- Cleveland Clinic Foundation
- Johns Hopkins University (RR025005)
- University of Texas Southwestern Medical Center
- Case Western Reserve University (UL1RR024989)
- Deutsches Krebsforschungszentrum
- Ministry of Education, India
- Stifterverband
- National Institutes of Health (RR024131, RR025005, RR05096, RR024989)
- University of Illinois at Urbana-Champaign
- University of California, San Francisco
- Leonard M. Miller School of Medicine
- National Institute on Aging (R01AG019712)
- National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK06102, R01DK076116, K24DK062234, U01DK060990, 5U01 DK60980, (P30-DK-07938, R01DK081374, R01DK062472, F30DK091057, K23DK081673, K23DK087858, R01DK091392, RR024986, R01DK091218, R01DK092461, U01DK060984, U01DK060902, U01DK060980, U01DK060963, U01DK061021, U01DK061028)
- National Center for Research Resources (UL1RR024131, RR-05096, UL1RR024989, UL1RR025005, RR 024131, M01RR016500, UL1RR024986, UL1RR024134, UL1RR029879, M01RR005096, M01RR 16500, M01RR000042)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- fibroblast growth factor 23, left ventricular hypertrophy, chronic kidney disease, calcineurin/NFAT signaling, fibroblast growth factor receptor, cardiomyocyte hypertrophy, cardiovascular disease
- MeSH terms
- Fibroblast Growth Factor-23, Klotho Proteins, Adult, Aged, Animals, Disease Models, Animal, Female, Fibroblast Growth Factors, Glucuronidase, Humans, Kidney Failure, Chronic, Male, Mice, Inbred C57BL, Middle Aged, Models, Cardiovascular, Prospective Studies, Recombinant Proteins, Cohort Studies, Signal Transduction, Fibroblast Growth Factor 2, Hypertrophy, Left Ventricular, Receptors, Fibroblast Growth Factor, Mice, Knockout, Myocytes, Cardiac, Mice, Rats, Young Adult
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