title: Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.
abstract: Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked to cardiovascular disease and all-cause mortality in chronic kidney disease. FGF23 rises in patients with CKD stages 2-3, but in patients with autosomal dominant polycystic kidney disease, the increase of FGF23 precedes the first measurable decline in renal function. The mechanisms governing FGF23 production and effects in kidney disease are largely unknown. Here we studied the relation between FGF23 and mineral homeostasis in two animal models of PKD. Plasma FGF23 levels were increased 10-fold in 4-week-old cy/+ Han:SPRD rats, whereas plasma urea and creatinine concentrations were similar to controls. Plasma calcium and phosphate levels as well as TmP/GFR were similar in PKD and control rats at all time points examined. Expression and activity of renal phosphate transporters, the vitamin D3-metabolizing enzymes, and the FGF23 co-ligand Klotho in the kidney were similar in PKD and control rats through 8 weeks of age, indicating resistance to FGF23, although phosphorylation of the FGF receptor substrate 2α protein was enhanced. In the kidneys of rats with PKD, FGF23 mRNA was highly expressed and FGF23 protein was detected in cells lining renal cysts. FGF23 expression in bone and spleen was similar in control rats and rats with PKD. Similarly, in an inducible Pkd1 knockout mouse model, plasma FGF23 levels were elevated, FGF23 was expressed in kidneys, but renal phosphate excretion was normal. Thus, the polycystic kidney produces FGF23 but is resistant to its action.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Spichtig
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland [2] Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Ivana
authors.initials: I
authors.lastname: Pavik
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Petzold
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.affiliation: Department of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lanja
authors.initials: L
authors.lastname: Saleh
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Ilka
authors.initials: I
authors.lastname: Edenhofer
authors.affiliation: 1] Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland [2] Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.affiliation: Center for Nephrology, Royal Free Hospital, University College London, London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jaeger
authors.affiliation: 1] Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland [2] Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation; D014508:Urea / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002117:Calcitriol; D002118:Calcium; D003404:Creatinine; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D050396:TRPP Cation Channels; D014508:Urea; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C505605:Fgf23 protein, rat; C552089:fibroblast receptor substrate 2, rat