title: 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.
abstract: Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1α-OHase and decreased 24-OHase expressions in the kidney. These antibody-induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25-dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion.
authors.affiliation: Innovative Drug Research Laboratories, Kyowa Hakko Kirin, Tokyo, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nagano
authors.forename: Itaru
authors.initials: I
authors.lastname: Urakawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Kousuke
authors.initials: K
authors.lastname: Iijima
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000009:adverse effects; D002118:Calcium / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000276:immunology / Q000378:metabolism*; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008903:Minerals / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; C505605:Fgf23 protein, rat; D008903:Minerals; D010281:Parathyroid Hormone; D010710:Phosphates; C051951:antiglomerular basement membrane antibody; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D002118:Calcium