{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:26:28Z","timestamp":1792009588954,"version":"4.4.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,8,19]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Recent studies have highlighted the deleterious role of high phosphate intake in hypertension via sympathetic overactivation, yet the underlying mechanisms remain unclear. Dietary phosphate loading triggers physiologic release of FGF23 (fibroblast growth factor\u201323) from the bone to maintain phosphate homeostasis. Both FGF23 and FGF receptors (FGFRs) are present in the central nervous system, but their role in neural control of blood pressure during phosphate loading is unknown. We investigated central FGF23\/FGFR signaling in high-phosphate diet\u2013induced sympathetic dysregulation of blood pressure in rats.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>FGF23 protein levels were measured by immunoprecipitation, immunoblotting, and immunohistochemistry. FGF23 translocation into the brain was determined by injecting infrared-labeled FGF23 intravenously into anesthetized Sprague-Dawley rats. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction were measured in decerebrate Sprague-Dawley rats treated with either a normal 0.6% phosphate diet (NP) or a high 1.2% phosphate diet (HP) for 12 weeks before and after intracerebroventricular (ICV) administration of FGFR signaling inhibitors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Excess phosphate intake significantly increased FGF23 protein levels in the brainstem (HP versus NP,\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.009) and cerebrospinal fluid (HP versus NP,\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.001). Peripheral injection of infrared-labeled FGF23 showed clear entry into the choroid plexus and medulla oblongata. ICV administration of PD173074, a pan-FGFR(1\u20134) inhibitor, significantly attenuated the heightened RSNA (\u0394=84\u00b153 versus 32\u00b125% [\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.0001]) and MAP (\u0394=35\u00b114 versus 9\u00b17 mm Hg [\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.0001]) responses to muscle contraction in HP animals, but did not affect the RSNA and MAP responses during stimulation in NP animals (\u0394RSNA=40\u00b129 versus 30\u00b122% and \u0394MAP=18\u00b113 versus 13\u00b19 mm Hg before versus after ICV injection). ICV injection of BLU9931, a relatively selective FGFR4 inhibitor, also decreased the responses in HP rats only (\u2206RSNA=112\u00b170 versus 65\u00b146% [\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.006] and \u2206MAP=41\u00b114 versus 20\u00b114 mm Hg [\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.0001] before versus after ICV injection). However, ICV administration of AZD4547, a FGFR1\u20133 inhibitor, and C-terminal FGF23 peptide, a competitive inhibitor of FGF23\/FGFR\/\u03b1-Klotho complex formation, did not alter the responses in either NP or HP animals.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Our data reveal a novel pathophysiologic paradigm of high-phosphate diet\u2013induced sympathoexcitation and hypertension by FGF23 crossing into the brain, possibly acting via FGFR4.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.071605","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:00:36Z","timestamp":1749099636000},"page":"450-464","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["High Dietary Phosphate Intake Induces Hypertension and Sympathetic Overactivation via Central Fibroblast Growth Factor Receptor Signaling"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1048-9543","authenticated-orcid":true,"given":"Han-Kyul","family":"Kim","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine\u2013Cardiology Division (H.-K.K., B.A.R., W.V.), University of Texas Southwestern Medical Center, Dallas."},{"name":"Applied Clinical Research (H.-K.K., A.F., S.A.S., M.M.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7322-043X","authenticated-orcid":true,"given":"Ayumi","family":"Fukazawa","sequence":"additional","affiliation":[{"name":"Applied Clinical Research (H.-K.K., A.F., S.A.S., M.M.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-2342","authenticated-orcid":true,"given":"Scott A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Applied Clinical Research (H.-K.K., A.F., S.A.S., M.M.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4455-8084","authenticated-orcid":true,"given":"Masaki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Applied Clinical Research (H.-K.K., A.F., S.A.S., M.M.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-6703","authenticated-orcid":true,"given":"Beverly A.","family":"Rothermel","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine\u2013Cardiology Division (H.-K.K., B.A.R., W.V.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4056-0526","authenticated-orcid":true,"given":"Teppei","family":"Fujikawa","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research (T.F., M.G., L.G.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Galvan","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research (T.F., M.G., L.G.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3609-7441","authenticated-orcid":true,"given":"Laurent","family":"Gautron","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research (T.F., M.G., L.G.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne V.","family":"Pastor","sequence":"additional","affiliation":[{"name":"Charles and Jane Pak Center for Mineral Metabolism and Clinical Research (J.V.P., I.J.C., O.W.M., W.V.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2563-4048","authenticated-orcid":true,"given":"Isabelle J.","family":"Carroll","sequence":"additional","affiliation":[{"name":"Charles and Jane Pak Center for Mineral Metabolism and Clinical Research (J.V.P., I.J.C., O.W.M., W.V.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9176-3414","authenticated-orcid":true,"given":"Orson W.","family":"Moe","sequence":"additional","affiliation":[{"name":"Internal Medicine\u2013Nephrology Division (O.W.M.), University of Texas Southwestern Medical Center, Dallas."},{"name":"Physiology (O.W.M.), University of Texas 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