NFκB-sensitive Orai1 expression in the regulation of FGF23 release
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Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFκB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFκB, which is known to upregulate Orai1, the Ca2+ channel accomplishing store-operated Ca2+ entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca2+ activity utilizing Fura-2-fluorescence, and SOCE from Ca2+ entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca2+ channel Orai1. SOCE was lowered by NFκB inhibitor wogonin as well as by Orai1 inhibitors 2-APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca2+ ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SK&F96365, by Orai1 silencing, as well as by NFκB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFκB-sensitive, store-operated Ca2+ entry.
Osteoblast UMR106 and IPO cells express Ca2+ channel Orai1.
Osteoblast store-operated Ca2+ entry is accomplished by NFκB-sensitive Orai1.
Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca2+ activity.
Fgf23 transcription is decreased by Orai inhibitors and Orai1 silencing.
Fgf23 transcription is lowered by NFκB inhibitors.
Keywords1,25(OH)2D3 SOCE Calcium Orai1 NFκB
The authors acknowledge the technical assistance of E. Faber. The study was supported by the Deutsche Forschungsgemeinschaft (La 315/15-1, Fo 695/1-1, and Fo 695/1-2) and the National Center for Competence in Research NCCR Kidney. CH was financed by the Swiss National Science Foundation.
MF and FL made the study design. BZ, JY, ATU, HF, AF, SS, MSS, HC, DA, DS, and AD performed data collection. BZ, JY, SS, and CAW analyzed the data. MF, CAW, and FL interpreted the results. FL drafted the manuscript. FL wrote the manuscript. MF, CAW, and FL revised the manuscript content. BZ, JY, ATU, HF, AF, SS, MSS, HC, DA, DS, AD, CAW, MF, and FL read and approved the final version of the manuscript. FL takes responsibility for the integrity of the data analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- 15.Imazu M, Takahama H, Asanuma H, Funada A, Sugano Y, Ohara T, Hasegawa T, Asakura M, Kanzaki H, Anzai T et al (2014) Pathophysiological impact of serum fibroblast growth factor 23 in patients with non-ischemic cardiac disease and early chronic kidney disease. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00331.2014 PubMedGoogle Scholar
- 17.Evenepoel P, Meijers B, Viaene L, Bammens B, Claes K, Kuypers D, Vanderschueren D, Vanrenterghem Y (2010) Fibroblast growth factor-23 in early chronic kidney disease: additional support in favor of a phosphate-centric paradigm for the pathogenesis of secondary hyperparathyroidism. Clin J Am Soc Nephrol 5:1268–1276CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Prie D, Forand A, Francoz C, Elie C, Cohen I, Courbebaisse M, Eladari D, Lebrec D, Durand F, Friedlander G (2013) Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One 8, e66182CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Zhao Y, Banerjee S, Dey N, LeJeune WS, Sarkar PS, Brobey R, Rosenblatt KP, Tilton RG, Choudhary S (2011) Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes 60:1907–1916CrossRefPubMedPubMedCentralGoogle Scholar