Inhibition of the over-activated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models, however it remains unknown how complement factor B (CFB) is up-regulated in ADPKD. Here we showed that the overexpression of complement factor B (CFB) in cystic kidneys associated with increased JAK2/STAT1 activity and enhanced expression of polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB up-regulation in renal tubular epithelial cells. Furthermore, PC1-CTT over-expression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose-dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB up-regulation in ADPKD and a novel role of PC1-CTT on ADPKD associated inflammation. Furthermore our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD.
- Complement Factor B (CFB)
- Polycystic Kidney Disease (PKD)
- polycystin-1 C-terminal tail (PC1-CTT)
- signal transducer and activator of transcription 1 (STAT1)
- Copyright © 2015, American Journal of Physiology - Renal Physiology