title: The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia.
abstract: Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats. Folic acid-induced acute kidney injury increased calvaria FGF23 mRNA and serum FGF23 and parathyroid hormone (PTH) levels at 6 h. The FGFR1 receptor inhibitor PD173074 prevented the folic acid-induced increase in both FGF23 mRNA and serum levels but had no effect on serum PTH levels. A more prolonged uremia due to an adenine high-phosphorus diet for 14 days resulted in high levels of FGF23 mRNA and serum FGF23 and PTH. PD173074 decreased serum FGF23 and mRNA levels with no effect on PTH in the adenine high phosphorus-induced uremic rats. Therefore, a derangement in FGF23 regulation starts early in the course of acute kidney injury, is in part independent of the increase in serum PTH, and involves activation of FGFR1. It is possible that FGFR1 in the osteocyte is activated by locally produced canonical FGFs, which are increased in uremia. This is the first demonstration that activation of FGFR1 is essential for the high levels of FGF23 in acute and chronic experimental uremia.
authors: Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Alia
authors: A
authors: Hassan
authors: Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Karina
authors: K
authors: Durlacher
authors: Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Justin
authors: J
authors: Silver
authors: Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Tally
authors: T
authors: Naveh-Many
authors: Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel ronenl@hadassah.org.il.
authors: Ronen
authors: R
authors: Levi
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D000225:Adenine; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000235:genetics; D005492:Folic Acid; D008297:Male; D008810:Mice, Inbred C57BL; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood; D016226:Phosphorus, Dietary; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012886:Skull / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D014511:Uremia / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: C000717428:Fgf23 protein, mouse; C115711:PD 173074; D010281:Parathyroid Hormone; D016226:Phosphorus, Dietary; D011743:Pyrimidines; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005492:Folic Acid; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000225:Adenine
keywords: FGF23; FGFR; acute kidney injury; uremia