{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T10:34:32Z","timestamp":1774866872404,"version":"3.50.1"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["F31DK115074"],"award-info":[{"award-number":["F31DK115074"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK076116"],"award-info":[{"award-number":["R01DK076116"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL128714"],"award-info":[{"award-number":["R01HL128714"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases"},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001463","name":"American Society of Nephrology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001463","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independently of \u03b1-klotho, the canonical co-receptor for FGF23 in the kidney, which stimulates left ventricular hypertrophy and hepatic production of inflammatory cytokines. FGF23 has also been shown to independently predict progression of renal disease, however, whether FGF23 and FGFR4 also contribute to CKD remains unknown. Here, we generated a mouse model with dual deletions of FGFR4 and \u03b1-klotho, and we induced CKD in mice with either global deletion or constitutive activation of FGFR4. We demonstrate that FGF23 is not capable of inducing phosphaturia via FGFR4 and that FGFR4 does not promote or mitigate renal injury in animal models of CKD. Taken together our results suggest FGFR4 inhibition as a safe alternative strategy to target cardiovascular disease and chronic inflammation in patients with CKD without interrupting the necessary phosphaturic effects of FGF23.<\/jats:p>","DOI":"10.1038\/s41598-019-50669-0","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T10:02:32Z","timestamp":1569924152000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["FGFR4 does not contribute to progression of chronic kidney disease"],"prefix":"10.1038","volume":"9","author":[{"given":"Ashlee","family":"Taylor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Yanucil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Musgrove","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melody","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shintaro","family":"Ide","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3285-8613","authenticated-orcid":false,"given":"Tomokazu","family":"Souma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Faul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1127-1442","authenticated-orcid":false,"given":"Myles","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5544-1896","authenticated-orcid":false,"given":"Alexander","family":"Grabner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"50669_CR1","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1038\/ki.2011.47","volume":"79","author":"T Isakova","year":"2011","unstructured":"Isakova, T. et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney International 79, 1370\u20131378 (2011).","journal-title":"Kidney International"},{"key":"50669_CR2","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. 121, 4393\u20134408 (2011).","journal-title":"J. Clin. Invest."},{"key":"50669_CR3","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 359, 584\u2013592 (2008).","journal-title":"N Engl J Med"},{"key":"50669_CR4","doi-asserted-by":"publisher","first-page":"2600","DOI":"10.1681\/ASN.2006080936","volume":"18","author":"D Fliser","year":"2007","unstructured":"Fliser, D. et al. Fibroblast Growth Factor 23 (FGF23) Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease (MMKD) Study. Journal of the American Society of Nephrology 18, 2600\u20132608 (2007).","journal-title":"Journal of the American Society of Nephrology"},{"key":"50669_CR5","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1681\/ASN.2012070713","volume":"24","author":"JJ Scialla","year":"2013","unstructured":"Scialla, J. J. et al. Mineral metabolites and CKD progression in African Americans. J. Am. Soc. Nephrol. 24, 125\u2013135 (2013).","journal-title":"J. Am. Soc. Nephrol."},{"key":"50669_CR6","first-page":"n\/a","volume":"51","author":"O Andrukhova","year":"2014","unstructured":"Andrukhova, O. et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 51, n\/a\u2013n\/a (2014).","journal-title":"EMBO Mol Med"},{"key":"50669_CR7","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/nature05315","volume":"444","author":"I Urakawa","year":"2006","unstructured":"Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770\u2013774 (2006).","journal-title":"Nature"},{"key":"50669_CR8","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. Cell Metabolism 22, 1020\u20131032 (2015).","journal-title":"Cell Metabolism"},{"key":"50669_CR9","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.kint.2016.05.019","volume":"90","author":"S Singh","year":"2016","unstructured":"Singh, S. et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney International 90, 985\u2013996 (2016).","journal-title":"Kidney International"},{"key":"50669_CR10","first-page":"F1","volume":"312","author":"V David","year":"2017","unstructured":"David, V., Francis, C. & Babitt, J. L. Ironing out the cross talk between FGF23 and inflammation. AJP: Renal Physiology 312, F1\u2013F8 (2017).","journal-title":"AJP: Renal Physiology"},{"key":"50669_CR11","doi-asserted-by":"publisher","unstructured":"Voelkl, J. et al. Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. J. Clin. Invest. 1\u201311, https:\/\/doi.org\/10.1172\/JCI64093 (2013).","DOI":"10.1172\/JCI64093"},{"key":"50669_CR12","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/36285","volume":"390","author":"M Kuro-o","year":"1997","unstructured":"Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45\u201351 (1997).","journal-title":"Nature"},{"key":"50669_CR13","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.biocel.2017.09.009","volume":"92","author":"ER Smith","year":"2017","unstructured":"Smith, E. R., Holt, S. G. & Hewitson, T. D. FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-\u03b2 autoinduction. International Journal of Biochemistry and Cell Biology 92, 63\u201378 (2017).","journal-title":"International Journal of Biochemistry and Cell Biology"},{"key":"50669_CR14","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1126\/science.aar2131","volume":"360","author":"J Park","year":"2018","unstructured":"Park, J. et al. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360, 758\u2013763 (2018).","journal-title":"Science"},{"key":"50669_CR15","doi-asserted-by":"publisher","first-page":"3562","DOI":"10.1096\/fj.09-152488","volume":"24","author":"M Ohnishi","year":"2010","unstructured":"Ohnishi, M. & Razzaque, M. S. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. The FASEB Journal 24, 3562\u20133571 (2010).","journal-title":"The FASEB Journal"},{"key":"50669_CR16","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1096\/fj.08-114397","volume":"23","author":"T Nakatani","year":"2009","unstructured":"Nakatani, T. et al. In vivogenetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. The FASEB Journal 23, 433\u2013441 (2009).","journal-title":"The FASEB Journal"},{"key":"50669_CR17","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1172\/JCI83470","volume":"126","author":"J Rossaint","year":"2016","unstructured":"Rossaint, J. et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J. Clin. Invest. 126, 962\u2013974 (2016).","journal-title":"J. Clin. Invest."},{"key":"50669_CR18","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 19, 2342\u20132350 (2008).","journal-title":"Journal of the American Society of Nephrology"},{"key":"50669_CR19","first-page":"E508","volume":"300","author":"H Li","year":"2011","unstructured":"Li, H., Martin, A., David, V. & Quarles, L. D. Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. AJP: Endocrinology and Metabolism 300, E508\u2013E517 (2011).","journal-title":"AJP: Endocrinology and Metabolism"},{"key":"50669_CR20","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. 122, 2543\u20132553 (2012).","journal-title":"J. Clin. Invest."},{"key":"50669_CR21","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/s41598-017-00462-8","volume":"7","author":"ER Smith","year":"2017","unstructured":"Smith, E. R., Tan, S.-J., Holt, S. G. & Hewitson, T. D. FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts. Scientific Reports 7, 737\u201314 (2017).","journal-title":"Scientific Reports"},{"key":"50669_CR22","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1681\/ASN.2015060613","volume":"27","author":"M Shi","year":"2016","unstructured":"Shi, M. et al. \u03b1Klotho Mitigates Progression of AKI to CKD through Activation of Autophagy. Journal of the American Society of Nephrology 27, 2331\u20132345 (2016).","journal-title":"Journal of the American Society of Nephrology"},{"issue":"5","key":"50669_CR23","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1016\/j.kint.2016.10.034","volume":"91","author":"Ming Chang Hu","year":"2017","unstructured":"Hu, M.-C. et al. Recombinant alpha Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney International 1\u201311, https:\/\/doi.org\/10.1016\/j.kint.2016.10.034 (2017).","journal-title":"Kidney International"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50669-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50669-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50669-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T14:02:37Z","timestamp":1671285757000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50669-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,1]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["50669"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-50669-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,1]]},"assertion":[{"value":"7 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare competing financial interests. M.W. served as a consultant to Akebia, Amag, Ardelyx, Diasorin, Pharmacosmos and C.F. served on the advisory board of Klotho Therapeutics and Calico. All other authors declare no potential conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14023"}}