FGF23 induces left ventricular hypertrophy

Christian Faul, Ansel P. Amaral, Behzad Oskouei, Ming C 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 & 15 others 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

Research output: Contribution to journalArticle

1028 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4393-4408
Number of pages16
JournalJournal of Clinical Investigation
Volume121
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Left Ventricular Hypertrophy
Chronic Renal Insufficiency
Fibroblast Growth Factor Receptors
Cardiovascular Diseases
Parathyroid Glands
Mortality
Calcineurin
Cardiac Myocytes
Intravenous Injections
Hypertrophy
Animal Models
Public Health
Blood Pressure
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Faul, C., Amaral, A. P., Oskouei, B., Hu, M. C., Sloan, A., Isakova, T., ... Wolf, M. (2011). FGF23 induces left ventricular hypertrophy. Journal of Clinical Investigation, 121(11), 4393-4408. https://doi.org/10.1172/JCI46122

FGF23 induces left ventricular hypertrophy. / Faul, Christian; Amaral, Ansel P.; Oskouei, Behzad; Hu, Ming C; Sloan, Alexis; Isakova, Tamara; Gutiérrez, Orlando M.; Aguillon-Prada, Robier; Lincoln, Joy; Hare, Joshua M.; Mundel, Peter; Morales, Azorides; Scialla, Julia; Fischer, Michael; Soliman, Elsayed Z.; Chen, Jing; Go, Alan S.; Rosas, Sylvia E.; Nessel, Lisa; Townsend, Raymond R.; Feldman, Harold I.; Sutton, Martin St John; Ojo, Akinlolu; Gadegbeku, Crystal; Di Marco, Giovana Seno; Reuter, Stefan; Kentrup, Dominik; Tiemann, Klaus; Brand, Marcus; Hill, Joseph A; Moe, Orson W; Kuro-o, Makoto; Kusek, John W.; Keane, Martin G.; Wolf, Myles.

In: Journal of Clinical Investigation, Vol. 121, No. 11, 01.11.2011, p. 4393-4408.

Research output: Contribution to journalArticle

Faul, C, Amaral, AP, Oskouei, B, Hu, MC, Sloan, A, Isakova, T, Gutiérrez, OM, Aguillon-Prada, R, Lincoln, J, Hare, JM, Mundel, P, Morales, A, Scialla, J, Fischer, M, Soliman, EZ, Chen, J, Go, AS, Rosas, SE, Nessel, L, Townsend, RR, Feldman, HI, Sutton, MSJ, Ojo, A, Gadegbeku, C, Di Marco, GS, Reuter, S, Kentrup, D, Tiemann, K, Brand, M, Hill, JA, Moe, OW, Kuro-o, M, Kusek, JW, Keane, MG & Wolf, M 2011, 'FGF23 induces left ventricular hypertrophy', Journal of Clinical Investigation, vol. 121, no. 11, pp. 4393-4408. https://doi.org/10.1172/JCI46122
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T et al. FGF23 induces left ventricular hypertrophy. Journal of Clinical Investigation. 2011 Nov 1;121(11):4393-4408. https://doi.org/10.1172/JCI46122
Faul, Christian ; Amaral, Ansel P. ; Oskouei, Behzad ; Hu, Ming C ; Sloan, Alexis ; Isakova, Tamara ; Gutiérrez, Orlando M. ; Aguillon-Prada, Robier ; Lincoln, Joy ; Hare, Joshua M. ; Mundel, Peter ; Morales, Azorides ; Scialla, Julia ; Fischer, Michael ; Soliman, Elsayed Z. ; Chen, Jing ; Go, Alan S. ; Rosas, Sylvia E. ; Nessel, Lisa ; Townsend, Raymond R. ; Feldman, Harold I. ; Sutton, Martin St John ; Ojo, Akinlolu ; Gadegbeku, Crystal ; Di Marco, Giovana Seno ; Reuter, Stefan ; Kentrup, Dominik ; Tiemann, Klaus ; Brand, Marcus ; Hill, Joseph A ; Moe, Orson W ; Kuro-o, Makoto ; Kusek, John W. ; Keane, Martin G. ; Wolf, Myles. / FGF23 induces left ventricular hypertrophy. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 11. pp. 4393-4408.
@article{91e3ec0897d24243a8760fd878787f1f,
title = "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.",
author = "Christian Faul and Amaral, {Ansel P.} and Behzad Oskouei and Hu, {Ming C} and Alexis Sloan and Tamara Isakova and Guti{\'e}rrez, {Orlando M.} and Robier Aguillon-Prada and Joy Lincoln and Hare, {Joshua M.} and Peter Mundel and Azorides Morales and Julia Scialla and Michael Fischer and Soliman, {Elsayed Z.} and Jing Chen and Go, {Alan S.} and Rosas, {Sylvia E.} and Lisa Nessel and Townsend, {Raymond R.} and Feldman, {Harold I.} and Sutton, {Martin St John} and Akinlolu Ojo and Crystal Gadegbeku and {Di Marco}, {Giovana Seno} and Stefan Reuter and Dominik Kentrup and Klaus Tiemann and Marcus Brand and Hill, {Joseph A} and Moe, {Orson W} and Makoto Kuro-o and Kusek, {John W.} and Keane, {Martin G.} and Myles Wolf",
year = "2011",
month = "11",
day = "1",
doi = "10.1172/JCI46122",
language = "English (US)",
volume = "121",
pages = "4393--4408",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

TY - JOUR

T1 - FGF23 induces left ventricular hypertrophy

AU - Faul, Christian

AU - Amaral, Ansel P.

AU - Oskouei, Behzad

AU - Hu, Ming C

AU - Sloan, Alexis

AU - Isakova, Tamara

AU - Gutiérrez, Orlando M.

AU - Aguillon-Prada, Robier

AU - Lincoln, Joy

AU - Hare, Joshua M.

AU - Mundel, Peter

AU - Morales, Azorides

AU - Scialla, Julia

AU - Fischer, Michael

AU - Soliman, Elsayed Z.

AU - Chen, Jing

AU - Go, Alan S.

AU - Rosas, Sylvia E.

AU - Nessel, Lisa

AU - Townsend, Raymond R.

AU - Feldman, Harold I.

AU - Sutton, Martin St John

AU - Ojo, Akinlolu

AU - Gadegbeku, Crystal

AU - Di Marco, Giovana Seno

AU - Reuter, Stefan

AU - Kentrup, Dominik

AU - Tiemann, Klaus

AU - Brand, Marcus

AU - Hill, Joseph A

AU - Moe, Orson W

AU - Kuro-o, Makoto

AU - Kusek, John W.

AU - Keane, Martin G.

AU - Wolf, Myles

PY - 2011/11/1

Y1 - 2011/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80555148939&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80555148939&partnerID=8YFLogxK

U2 - 10.1172/JCI46122

DO - 10.1172/JCI46122

M3 - Article

VL - 121

SP - 4393

EP - 4408

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 11

ER -