The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1
The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1
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Polycystin-1 C 末端尾部通过信号转导子和转录激活子 1 调节补体因子 B 表达
DOI：
10.1152/ajprenal.00428.2015
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发表时间：
2016
影响因子：
4.2
通讯作者：
Mei Changlin
中科院分区：
文献类型：
--
作者：
Wu Ming;Chen Meihan;Jing Ying;Gu Junhui;Mei Shuqin;Yao Qing;Zhou Jie;Yang Ming;Sun Lijun;Wang Wutao;Hu Huimin;Wuthrich Rudolf P.;Mei Changlin
在动物模型中，抑制常染色体显性多囊肾病（ADPKD）中过度激活的替代补体途径可延缓疾病进展然而，补体因子B （CFB）在ADPKD中的上调机制尚不清楚。在这里，我们发现CFB在囊肾中的过表达与JAK2/STAT1活性增加和多囊素-1 c末端尾部（PC1-CTT）表达增强有关。STAT1过表达或阻断可增加或降低CFB表达和CFB启动子活性。此外，PC1-CTT过表达诱导肾小管上皮细胞JAK2/STAT1活化和CFB上调。此外，PC1-CTT过表达增加了人CFB启动子活性，而显性的STAT1阴性质粒或假定的STAT1应答元件突变降低了PC1-CTT诱导的CFB启动子活性。在小鼠巨噬细胞系上检测了CFB对巨噬细胞分化的影响。生物活性CFB剂量依赖性地促进巨噬细胞M2表型转化。此外，来自肾上皮细胞的条件培养基促进巨噬细胞M2表型转化，这种转化被STAT1抑制以剂量依赖的方式阻断。pc1 - ctt转染肾上皮细胞的条件培养基进一步促进巨噬细胞M2表型转化，氟达拉滨或CFB抗体抑制了这种转化。此外，我们发现NF-κB作用于PC1-CTT的下游，可能部分介导PC1-CTT诱导的CFB表达。总之，我们的研究揭示了CFB在ADPKD中上调的可能机制以及PC1-CTT在ADPKD相关炎症中的新作用。此外，我们的研究表明，靶向STAT1可能是预防ADPKD患者肾脏炎症的新策略。
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.