title: The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1.
abstract: Inhibition of the overactivated 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 upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the 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 upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression 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 a 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 upregulation in ADPKD and a novel role of PC1-CTT in 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.
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China; chlmei1954@126.com.
authors.forename: Meihan
authors.initials: M
authors.lastname: Chen
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China; Department of Blood Purification, General Hospital of Jinan Military Command of PLA, Shandong, China; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Junhui
authors.initials: J
authors.lastname: Gu
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Shuqin
authors.initials: S
authors.lastname: Mei
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Wutao
authors.initials: W
authors.lastname: Wang
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.affiliation: Division of Nephrology, University Hospital, Zurich, Switzerland.
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.affiliation: Kidney Institute, Department of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China;
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D011415:Complement Factor B; D053614:Janus Kinase 2; D050794:STAT1 Transcription Factor; D050396:TRPP Cation Channels
keywords: Janus kinase 2 (JAK2); complement; kidney; macrophage; polycystic kidney disease (PKD); polycystin-1 C-terminal tail (PC1-CTT); signal transducer and activator of transcription 1 (STAT1)