{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T16:43:03Z","timestamp":1794588183263,"version":"4.9.1"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,16]],"date-time":"2017-05-16T00:00:00Z","timestamp":1494892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,16]],"date-time":"2017-05-16T00:00:00Z","timestamp":1494892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed. Here, we report that FGF23-induced cardiac hypertrophy is reversible <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> upon removal of the hypertrophic stimulus. Specific blockade of FGFR4 attenuates established LVH in the 5\/6 nephrectomy rat model of CKD. Since CKD mimics a form of accelerated cardiovascular aging, we also studied age-related cardiac remodeling. We show that aging mice lacking FGFR4 are protected from LVH. Finally, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation do not require FGFR4. Taken together, our data highlight a role of FGF23\/FGFR4 signaling in the regulation of cardiac remodeling and function, and indicate that pharmacological interference with cardiac FGF23\/FGFR4 signaling might protect from CKD- and age-related LVH.<\/jats:p>","DOI":"10.1038\/s41598-017-02068-6","type":"journal-article","created":{"date-parts":[[2017,5,10]],"date-time":"2017-05-10T15:03:16Z","timestamp":1494428596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["FGF23\/FGFR4-mediated left ventricular hypertrophy is reversible"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5544-1896","authenticated-orcid":false,"given":"Alexander","family":"Grabner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Schramm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neerupma","family":"Silswal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Hendrix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Yanucil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Czaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurav","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1127-1442","authenticated-orcid":false,"given":"Myles","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Stypmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovana Seno","family":"Di Marco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Wacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Faul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,16]]},"reference":[{"key":"2068_CR1","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/S0140-6736(13)60439-0","volume":"382","author":"K-U Eckardt","year":"2013","unstructured":"Eckardt, K.-U. et al. Evolving importance of kidney disease: from subspecialty to global health burden. The Lancet \n                           382, 158\u2013169, doi:10.1016\/S0140-6736(13)60439-0 (2013).","journal-title":"The Lancet"},{"key":"2068_CR2","doi-asserted-by":"publisher","first-page":"755","DOI":"10.2215\/CJN.02730608","volume":"4","author":"PS Parfrey","year":"2009","unstructured":"Parfrey, P. S., Lauve, M., Latremouille-Viau, D. & Lefebvre, P. Erythropoietin Therapy and Left Ventricular Mass Index in CKD and ESRD Patients: A Meta-Analysis. Clinical Journal of the American Society of Nephrology \n                           4, 755\u2013762, doi:10.2215\/CJN.02730608 (2009).","journal-title":"Clinical Journal of the American Society of Nephrology"},{"key":"2068_CR3","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1001\/jama.293.14.1737","volume":"293","author":"MG Shlipak","year":"2005","unstructured":"Shlipak, M. G. et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA \n                           293, 1737\u20131745, doi:10.1001\/jama.293.14.1737 (2005).","journal-title":"JAMA"},{"key":"2068_CR4","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1161\/CIRCULATIONAHA.108.844506","volume":"119","author":"OM Guti\u00e9rrez","year":"2009","unstructured":"Guti\u00e9rrez, O. M. et al. Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease. Circulation \n                           119, 2545\u20132552, doi:10.1161\/CIRCULATIONAHA.108.844506 (2009).","journal-title":"Circulation"},{"key":"2068_CR5","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/nrendo.2009.196","volume":"5","author":"MS Razzaque","year":"2009","unstructured":"Razzaque, M. S. The FGF23\u2013Klotho axis: endocrine regulation of phosphate homeostasis. Nature Reviews Endocrinology \n                           5, 611\u2013619, doi:10.1038\/nrendo.2009.196 (2009).","journal-title":"Nature Reviews Endocrinology"},{"key":"2068_CR6","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/ki.2012.176","volume":"82","author":"M Wolf","year":"2012","unstructured":"Wolf, M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney International \n                           82, 737\u2013747, doi:10.1038\/ki.2012.176 (2012).","journal-title":"Kidney International"},{"key":"2068_CR7","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1056\/NEJMoa0706130","volume":"359","author":"OM Guti\u00e9rrez","year":"2008","unstructured":"Guti\u00e9rrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med \n                           359, 584\u2013592, doi:10.1056\/NEJMoa0706130 (2008).","journal-title":"N Engl J Med"},{"key":"2068_CR8","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.atherosclerosis.2009.05.013","volume":"207","author":"MAI Mirza","year":"2009","unstructured":"Mirza, M. A. I., Larsson, A., Melhus, H., Lind, L. & Larsson, T. E. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis \n                           207, 546\u2013551, doi:10.1016\/j.atherosclerosis.2009.05.013 (2009).","journal-title":"Atherosclerosis"},{"key":"2068_CR9","doi-asserted-by":"publisher","first-page":"640","DOI":"10.7326\/0003-4819-152-10-201005180-00004","volume":"152","author":"BD Parker","year":"2010","unstructured":"Parker, B. D. 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. Ann. Intern. Med. \n                           152, 640\u2013648, doi:10.7326\/0003-4819-152-10-201005180-00004 (2010).","journal-title":"Ann. Intern. Med."},{"key":"2068_CR10","doi-asserted-by":"publisher","first-page":"4393","DOI":"10.1172\/JCI46122","volume":"121","author":"C Faul","year":"2011","unstructured":"Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. \n                           121, 4393\u20134408, doi:10.1172\/JCI46122 (2011).","journal-title":"J. Clin. Invest."},{"key":"2068_CR11","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1016\/j.cmet.2015.09.002","volume":"22","author":"A Grabner","year":"2015","unstructured":"Grabner, A. et al. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. 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FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. AJP: Endocrinology and Metabolism \n                           307, E426\u2013E436, doi:10.1152\/ajpendo.00264.2014 (2014).","journal-title":"AJP: Endocrinology and Metabolism"},{"key":"2068_CR22","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1093\/ndt\/gfu190","volume":"29","author":"GS Di Marco","year":"2014","unstructured":"Di Marco, G. S. et al. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrology Dialysis Transplantation \n                           29, 2028\u20132035, doi:10.1093\/ndt\/gfu190 (2014).","journal-title":"Nephrology Dialysis Transplantation"},{"key":"2068_CR23","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1053\/ajkd.2002.36881","volume":"40","author":"AG Stack","year":"2002","unstructured":"Stack, A. G. & Saran, R. Clinical correlates and mortality impact of left ventricular hypertrophy among new ESRD patients in the United States. Am. J. Kidney Dis. \n                           40, 1202\u20131210, doi:10.1053\/ajkd.2002.36881 (2002).","journal-title":"Am. J. Kidney Dis."},{"key":"2068_CR24","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.1097\/01.ASN.0000130566.69170.5E","volume":"15","author":"LP McMahon","year":"2004","unstructured":"McMahon, L. P. Development, Prevention, and Potential Reversal of Left Ventricular Hypertrophy in Chronic Kidney Disease. Journal of the American Society of Nephrology \n                           15, 1640\u20131647, doi:10.1097\/01.ASN.0000130566.69170.5E (2004).","journal-title":"Journal of the American Society of Nephrology"},{"key":"2068_CR25","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1097\/00007890-200008270-00006","volume":"70","author":"C Rigatto","year":"2000","unstructured":"Rigatto, C., Foley, R. N., Kent, G. M., Guttmann, R. & Parfrey, P. S. Long-term changes in left ventricular hypertrophy after renal transplantation. Transplantation \n                           70, 570\u2013575, doi:10.1097\/00007890-200008270-00006 (2000).","journal-title":"Transplantation"},{"key":"2068_CR26","doi-asserted-by":"publisher","first-page":"e82979","DOI":"10.1371\/journal.pone.0082979","volume":"8","author":"SN Cilvik","year":"2013","unstructured":"Cilvik, S. N. et al. Fibroblast Growth Factor Receptor 1 Signaling in Adult Cardiomyocytes Increases Contractility and Results in a Hypertrophic Cardiomyopathy. PLoS ONE \n                           8, e82979\u201317, doi:10.1371\/journal.pone.0082979 (2013).","journal-title":"PLoS ONE"},{"key":"2068_CR27","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1172\/JCI61405","volume":"122","author":"V Shalhoub","year":"2012","unstructured":"Shalhoub, V. et al. FGF23 neutralization improves chronic kidney disease\u2013associated hyperparathyroidism yet increases mortality. J. Clin. Invest. \n                           122, 2543\u20132553, doi:10.1172\/JCI61405 (2012).","journal-title":"J. Clin. Invest."},{"key":"2068_CR28","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1093\/toxsci\/kft161","volume":"135","author":"GM Yanochko","year":"2013","unstructured":"Yanochko, G. M. et al. Pan-FGFR Inhibition Leads to Blockade of FGF23 Signaling, Soft Tissue Mineralization, and Cardiovascular Dysfunction. Toxicological Sciences \n                           135, 451\u2013464, doi:10.1093\/toxsci\/kft161 (2013).","journal-title":"Toxicological Sciences"},{"key":"2068_CR29","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1681\/ASN.2007121301","volume":"19","author":"S Liu","year":"2008","unstructured":"Liu, S., Vierthaler, L., Tang, W., Zhou, J. & Quarles, L. D. FGFR3 and FGFR4 Do not Mediate Renal Effects of FGF23. Journal of the American Society of Nephrology \n                           19, 2342\u20132350, doi:10.1681\/ASN.2007121301 (2008).","journal-title":"Journal of the American Society of Nephrology"},{"key":"2068_CR30","doi-asserted-by":"publisher","first-page":"F351","DOI":"10.1152\/ajprenal.00232.2013","volume":"306","author":"J Gattineni","year":"2014","unstructured":"Gattineni, J. et al. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. AJP: Renal Physiology \n                           306, F351\u2013F358, doi:10.1152\/ajprenal.00232.2013 (2014).","journal-title":"AJP: Renal Physiology"},{"key":"2068_CR31","doi-asserted-by":"publisher","first-page":"64649","DOI":"10.18632\/oncotarget.11623","volume":"7","author":"H Hao","year":"2016","unstructured":"Hao, H. et al. FGF23 promotes myocardial fibrosis in mice through activation of \u03b2-catenin. Oncotarget \n                           7, 64649\u201364664, doi:10.18632\/oncotarget.11623 (2016).","journal-title":"Oncotarget"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02068-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02068-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02068-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T04:17:06Z","timestamp":1671769026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02068-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,16]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2068"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-02068-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,16]]},"assertion":[{"value":"1 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"C.F. has served as a consultant or received honoraria from Ultragenyx and has received research support from U3 Pharma GmbH and Roche. M.W. has served as a consultant or received honoraria from Ultragenyx, Amgen, Keryx, Lutipold, Pfizer and Sanofi. All other authors have declared that no conflict of interest exists.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1993"}}