Abstract: SA-PO386
FGF23 Promotes Progression of CKD by Directly Activating Pro-Inflammatory Signaling in Renal Epithelial Cells
Session Information
- CKD: Risk Factors for Incidence and Progression - III
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Chronic Kidney Disease (Non-Dialysis)
- 301 CKD: Risk Factors for Incidence and Progression
Authors
- Andrukhova, Olena, University of Veterinary Medicine of Vienna, Vienna, Austria
- Endler, Lukas, University of Veterinary Medicine, Vienna, Austria
- Strobl, Birgit, University of Veterinary Medicine of Vienna, Vienna, Austria
- Erben, Reinhold, University of Veterinary Medicine of Vienna, Vienna, Austria
Background
There is solid evidence from several clinical and epidemiological studies that fibroblast growth factor 23 (FGF23) is a strong predictor of disease progression and adverse outcomes in patients with chronic kidney disease (CKD). However, the mechanisms underlying the association between FGF23 and CKD progression are unclear.
Methods
To gain more insight into the signaling mechanisms induced by FGF23 in renal epithelial cells, we treated 3-month-old wild-type (WT) mice, Fgf23-/-/VDR (Fgf23/VDR; VDR, vitamin D receptor), and Klotho-/-/VDR (Klotho/VDR) compound mutant mice with recombinant FGF23 (rFGF23), harvested proximal and distal renal tubules by laser capture microdissection 2 and 8 hours after treatment, and performed mRNA expression profiling by next generation sequencing (RNA-Seq).
Results
RNA-Seq analysis revealed that rFGF23 treatment led to strong activation of the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway in proximal and distal renal epithelium in a Klotho independent fashion. This unexpected and striking finding was confirmed by qRT-PCR and immunohistochemical analysis of the Jak/STAT pathway. In vitro experiments using murine primary renal epithelial cells revealed that rFGF23 rapidly and Klotho-independently activates Jak/STAT signaling in a largely FGF receptor-3 dependent fashion. To analyze the role of FGF23-induced pro-inflammatory signaling in CKD pathology, we used 5/6-nephrectomized (5/6-Nx) mice as a disease model. CKD mice were characterized by high circulating concentrations of intact Fgf23, activation of renal Jak/STAT signaling, and renal interstitial fibrosis, 8 weeks after 5/6-Nx. Treatment of CKD mice with low doses of neutralizing anti-Fgf23 antibody (50 µg per mouse, two times per week) over 8 weeks largely prevented CKD progression, and profoundly reduced the Jak/STAT-mediated pro-inflammatory and pro-fibrotic pathways in a Klotho independent manner.
Conclusion
In conclusion, our study identified excessive FGF23 signaling as a pro-inflammatory factor, directly acting on renal epithelial cells to promote inflammation and fibrosis in the diseased kidney.
Funding
- Government Support - Non-U.S.