Föller, Michael

Lang, Florian

Spichtig, Daniela

Wagner, Carsten A.

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RENAL DEVELOPMENTAND CYSTICDISEASESFP063 INFLAMMATION TRIGGERS RENAL EXPRESSION OF FGF23IN POLYCYSTIC KIDNEY DISEASEDaniela Spichtig1, Michael Föller2, Florian Lang2 and Carsten AWagner11University of Zurich, Institute of Physiology, Zurich, Switzerland, 2University ofTübingen, Department of Physiology, Tübingen, GermanyIntroduction and Aims: Fibroblast growth factor 23 (FGF23) regulates phosphatehomeostasis and is directly linked to all-cause mortality in chronic kidney disease(CKD). FGF23 rises in patients with CKD stages 2-3 whereas in patients withautosomal dominant polycystic kidney disease (ADPKD), the increase of FGF23precedes the first measurable decline in renal function. Similar, in PKD animal modelssuch as Han:SPRD rats and Pkd1 conditional KO mice plasma FGF23 levels areelevated while renal function and phosphate homeostasis are unchanged. FGF23 ismainly expressed in bone but in PKD animals also the polycystic kidney is a source ofFGF23 production. In this study, we examined hypoxia and inflammation as possiblefactors regulating FGF23 expression in cyst lining epithelial cells of polycystic kidneys.Methods: Using Pkd1 conditional KO mice as well as bone cell models we investigatedthe regulation of renal FGF23 expression in PKD.Results: Renal FGF23 expression in Pkd1 conditional KO mice was accompanied byup-regulation of bone marker genes such as dentin matrix protein 1 and runt-relatedtranscription factor 2 as well as nuclear receptor related 1 protein (Nurr1) transcriptionfactor. Nurr1 is known to modulate FGF23 expression in bone and can be activated byPTH or Vitamin D as well as inflammatory markers such as tumor necrosis factor(TNFa). Primary bone cells treated in vitro with TNFa or lipopolysaccharides showedincreased FGF23 mRNA expression levels. TNFa mRNA expression was highlyupregulated in polycystic kidneys of Pkd1 conditional KO mice where it could be atrigger for renal FGF23 expression.It has been shown that in iron deprived mice as well as in UMR106 osteosarcoma cellsFGF23 expression is regulated by hypoxia. Hypoxia is present in cystic kidneys ofhuman as well as PKD animals. We found that MC3T3-E1 mouse preosteoblast cellline did not display intrinsic FGF23 expression. Nevertheless after two weeksdifferentiation of MC3T3-E1 along the osteogenic lineage FGF23 expression could beinduced by 1.25 (OH)2 vitamin D3. Vitamin D3 induced FGF23 expression was totallyrepressed when cells were cultured for 24 or 48h under hypoxic conditions. Primarybone cells intrinsically expressed FGF23 but expression levels were unchanged underhypoxic conditions.Conclusions: In conclusion, inflammation but not hypoxia could be a trigger for renalFGF23 expression in polycystic kidney disease.© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.Nephrology Dialysis Transplantation 30 (Supplement 3): iii80–iii88, 2015doi:10.1093/ndt/gfv167.19

FP063INFLAMMATION TRIGGERS RENAL EXPRESSION OF FGF23 IN POLYCYSTIC KIDNEY DISEASE

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FP063INFLAMMATION TRIGGERS RENAL EXPRESSION OF FGF23 IN POLYCYSTIC KIDNEY DISEASE

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