FGF23 induces left ventricular hypertrophy.

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.

[1]  H. Pavenstädt,et al.  Cardioprotective effect of calcineurin inhibition in an animal model of renal disease. , 2011, European heart journal.

[2]  Jiang He,et al.  Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. , 2011, JAMA.

[3]  Huiliang Xie,et al.  Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. , 2011, Kidney international.

[4]  M. Kuro-o,et al.  Klotho deficiency causes vascular calcification in chronic kidney disease. , 2011, Journal of the American Society of Nephrology : JASN.

[5]  T. Shimada,et al.  Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. , 2010, Kidney international.

[6]  M. Wolf,et al.  Forging forward with 10 burning questions on FGF23 in kidney disease. , 2010, Journal of the American Society of Nephrology : JASN.

[7]  L. Schurgers,et al.  The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study , 2010, Annals of Internal Medicine.

[8]  N. Lane,et al.  Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease. , 2010, American journal of physiology. Renal physiology.

[9]  M. Wolf,et al.  Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. , 2010, The Journal of clinical endocrinology and metabolism.

[10]  V. Jorgetti,et al.  Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[11]  J. Silver,et al.  Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. , 2010, Kidney international.

[12]  H. Melhus,et al.  Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. , 2009, Atherosclerosis.

[13]  C. Chazot,et al.  High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[14]  Thomas J. Wang,et al.  Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease , 2009, Circulation.

[15]  X. Bigard,et al.  Stimulus specific changes of energy metabolism in hypertrophied heart. , 2009, Journal of molecular and cellular cardiology.

[16]  M. Kuro-o,et al.  The Klotho gene family as a regulator of endocrine fibroblast growth factors , 2009, Molecular and Cellular Endocrinology.

[17]  E. Olson,et al.  Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. , 2008, The Journal of clinical investigation.

[18]  Anthony J. Muslin,et al.  MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. , 2008, Clinical science.

[19]  Kwanghee Kim,et al.  The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A , 2008, Nature Medicine.

[20]  M. Wolf,et al.  Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. , 2008, The New England journal of medicine.

[21]  J. Aubin,et al.  Overexpression of Fibroblast Growth Factor 23 Suppresses Osteoblast Differentiation and Matrix Mineralization In Vitro , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[23]  J. Coresh,et al.  Prevalence of chronic kidney disease in the United States. , 2007, JAMA.

[24]  Protein Kinase A, Ca2+/Calmodulin-Dependent Kinase II, and Calcineurin Regulate the Intracellular Trafficking of Myopodin between the Z-Disc and the Nucleus of Cardiac Myocytes , 2007, Molecular and Cellular Biology.

[25]  Ido Amit,et al.  Regulation of MAPKs by growth factors and receptor tyrosine kinases. , 2007, Biochimica et biophysica acta.

[26]  R. Kist,et al.  Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. , 2007, Developmental biology.

[27]  S. Kliewer,et al.  Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members , 2007, Molecular and Cellular Biology.

[28]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[29]  J. Molkentin,et al.  Regulation of cardiac hypertrophy by intracellular signalling pathways , 2006, Nature Reviews Molecular Cell Biology.

[30]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[31]  Richard B Devereux,et al.  Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardio , 2005, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[32]  K. White,et al.  Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. , 2005, Endocrinology.

[33]  Joshua M Hare,et al.  Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Rolla,et al.  Left ventricular hypertrophy in nondiabetic predialysis CKD. , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[35]  M. Wolf,et al.  Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. , 2005, Journal of the American Society of Nephrology : JASN.

[36]  R. Singer,et al.  Promotion of importin α–mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3 , 2005, The Journal of cell biology.

[37]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[38]  G. Dorn,et al.  Protein kinase cascades in the regulation of cardiac hypertrophy. , 2005, The Journal of clinical investigation.

[39]  K. Lorenz,et al.  The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy , 2004, Nature Medicine.

[40]  J. Molkentin,et al.  Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. , 2004, Biochemical and biophysical research communications.

[41]  Charles E McCulloch,et al.  Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. , 2004, The New England journal of medicine.

[42]  J. Molkentin.  Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. , 2004, Cardiovascular research.

[43]  Zhi-Sheng Jiang,et al.  Fibroblast growth factor 2 isoforms and cardiac hypertrophy. , 2004, Cardiovascular research.

[44]  C. Zoccali,et al.  Prognostic value of echocardiographic indicators of left ventricular systolic function in asymptomatic dialysis patients. , 2004, Journal of the American Society of Nephrology : JASN.

[45]  T. Blundell,et al.  The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. , 2004, Biochemistry.

[46]  J. Schaper,et al.  The Cytoskeleton and Related Proteins in the Human Failing Heart , 2000, Heart Failure Reviews.

[47]  E. Olson,et al.  Cardiac hypertrophy: the good, the bad, and the ugly. , 2003, Annual review of physiology.

[48]  Rick B. Vega,et al.  Control of Cardiac Growth and Function by Calcineurin Signaling* , 2003, Journal of Biological Chemistry.

[49]  S. Fukumoto,et al.  Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. , 2003, The New England journal of medicine.

[50]  A. Go,et al.  The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods. , 2003, Journal of the American Society of Nephrology : JASN.

[51]  D. Miao,et al.  The Autosomal Dominant Hypophosphatemic Rickets R176Q Mutation in Fibroblast Growth Factor 23 Resists Proteolytic Cleavage and Enhances in Vivo Biological Potency* , 2003, The Journal of Biological Chemistry.

[52]  E. Kardami,et al.  Biological activities of fibroblast growth factor-2 in the adult myocardium. , 2003, Cardiovascular research.

[53]  G. Crabtree,et al.  NFAT Signaling Choreographing the Social Lives of Cells , 2002, Cell.

[54]  E. Olson,et al.  Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[55]  E. Olson,et al.  Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Blacher,et al.  Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. , 2001, Journal of the American Society of Nephrology : JASN.

[57]  C. Zoccali,et al.  Prognostic impact of the indexation of left ventricular mass in patients undergoing dialysis. , 2001, Journal of the American Society of Nephrology : JASN.

[58]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[59]  R. Foley,et al.  Left ventricular hypertrophy in the renal patient. , 2001, Journal of the American Society of Nephrology : JASN.

[60]  Nobuyuki Itoh,et al.  Fibroblast growth factors , 2001, Genome Biology.

[61]  R. Kitsis,et al.  The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice , 2000, The EMBO journal.

[62]  E. Morkin.  Control of cardiac myosin heavy chain gene expression , 2000, Microscopy research and technique.

[63]  P. Kang,et al.  The conserved phosphoinositide 3‐kinase pathway determines heart size in mice , 2000, The EMBO journal.

[64]  D. Ornitz,et al.  FGFs, heparan sulfate and FGFRs: complex interactions essential for development. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[65]  D. Kelly,et al.  Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. , 1999, The American journal of the medical sciences.

[66]  S. Hubbard,et al.  Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain , 1998, The EMBO journal.

[67]  Iris,et al.  Basic fibroblast growth factor induces myocardial hypertrophy following acute infarction in rats , 1998, Experimental physiology.

[68]  A. Clerk,et al.  "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. , 1998, Circulation research.

[69]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[70]  Tadashi Kaname,et al.  Mutation of the mouse klotho gene leads to a syndrome resembling ageing , 1997, Nature.

[71]  A. Mebazaa,et al.  Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy. , 1997, Circulation research.

[72]  J. Fahey,et al.  Cardiovascular abnormalities in patients with X-linked hypophosphatemia. , 1997, The Journal of clinical endocrinology and metabolism.

[73]  S. Hughes,et al.  Differential Expression of the Fibroblast Growth Factor Receptor (FGFR) Multigene Family in Normal Human Adult Tissues , 1997, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[74]  C. MacArthur,et al.  Receptor Specificity of the Fibroblast Growth Factor Family* , 1996, The Journal of Biological Chemistry.

[75]  R. Foley,et al.  IMPACT OF RENAL TRANSPLANTATION ON UREMIC CARDIOMYOPATHY , 1995, Transplantation.

[76]  David C. Murray,et al.  Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. , 1995, Kidney international.

[77]  J. Molkentin,et al.  Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene , 1994, Molecular and cellular biology.

[78]  P. Parker,et al.  Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. , 1994, The Journal of biological chemistry.

[79]  Y. Yazaki,et al.  Control of cardiac gene expression by mechanical stress. , 1993, Annual review of physiology.

[80]  M. Jaye,et al.  Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. , 1992, Biochimica et biophysica acta.

[81]  T. Parker,et al.  Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. , 1990, The Journal of clinical investigation.

[82]  D E Manyari,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.

[83]  R. Biagini,et al.  Comparative toxicity of allylamine and acrolein in cultured myocytes and fibroblasts from neonatal rat heart. , 1989, Toxicology.

[84]  P. Simpson,et al.  Induction of the skeletal alpha-actin gene in alpha 1-adrenoceptor-mediated hypertrophy of rat cardiac myocytes. , 1987, The Journal of clinical investigation.

[85]  R. Matsuoka,et al.  Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. , 1987, The Journal of clinical investigation.

[86]  E. Lakatta,et al.  Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. , 1982, The American journal of physiology.

[87]  D. Fischman,et al.  Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro , 1982, The Journal of cell biology.

[88]  B. Swynghedauw,et al.  Myosin isoenzyme redistribution in chronic heart overload , 1979, Nature.

[89]  W. Nichols,et al.  Reversible depression in myocardial performance in dogs with experimental phosphorus deficiency. , 1978, The Journal of clinical investigation.

[90]  W. Wheeler,et al.  Effect of hypophosphatemia on myocardial performance in man. , 1977, The New England journal of medicine.