Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease.
Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease.
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DOI：
10.1152/ajprenal.00346.2017
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发表时间：
2018-07
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通讯作者：
Erin E. Olsan;J. West;Jacob A Torres;Nicholas Doerr;T. Weimbs
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作者：
Erin E. Olsan;J. West;Jacob A Torres;Nicholas Doerr;T. Weimbs
常染色体显性多囊肾病（ADPKD）是一种危及生命的、高度流行的单基因疾病，85%的患者由多囊蛋白-1（PC 1）突变引起。我们先前已经鉴定了PC 1的COOH末端切割片段，PC 1-p30，其与转录因子STAT 6相互作用以促进转录。STAT 6在PKD小鼠模型和人ADPKD中异常活跃，并且STAT 6的遗传去除或药理学抑制减弱疾病进展。在PKD小鼠模型的囊肿液中发现高水平的IL-13（一种STAT 6激活细胞因子），并且在ADPKD患者组织中发现增加的IL-13受体，这表明在IL-13和STAT 6之间存在正反馈回路，其在囊性上皮细胞中被激活并有助于疾病进展。在这项研究中，我们的目的是确定由STAT 6异常调节的基因，以更好地了解IL-13/STAT 6信号转导的增加如何促进PKD的进展。我们证明，骨膜蛋白，半乳糖凝集素-3，IL-24的表达上调，在各种形式的PKD和它们的异常调节介导的IL-13和STAT 6活性。骨膜蛋白和半乳糖凝集素-3先前已涉及PKD进展。我们通过显示在肾上皮细胞中IL-13处理后骨膜蛋白表达增加、在体内注射IL-13后半乳糖凝集素-3表达增加以及在小鼠和人肾细胞中IL-13处理和PC 1-p30过表达上调IL-24表达来支持这些发现。总的来说，这些发现提供了对IL-13/STAT 6信号传导增加促进PKD进展的可能机制的深入了解，并提出了潜在的治疗靶点。
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening, highly prevalent monogenic disease caused by mutations in polycystin-1 (PC1) in 85% of patients. We have previously identified a COOH-terminal cleavage fragment of PC1, PC1-p30, which interacts with the transcription factor STAT6 to promote transcription. STAT6 is aberrantly active in PKD mouse models and human ADPKD, and genetic removal or pharmacological inhibition of STAT6 attenuates disease progression. High levels of IL-13, a STAT6-activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL-13 receptors in ADPKD patient tissue, suggesting that a positive feedback loop exists between IL-13 and STAT6 is activated in cystic epithelial cells and contributes to disease progression. In this study, we aimed to identify genes aberrantly regulated by STAT6 to better understand how increased IL-13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3, and IL-24 is upregulated in various forms of PKD and that their aberrant regulation is mediated by IL-13 and STAT6 activity. Periostin and galectin-3 have previously been implicated in PKD progression. We support these findings by showing that periostin expression is increased after IL-13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL-13 in vivo and that IL-24 expression is upregulated by both IL-13 treatment and PC1-p30 overexpression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL-13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets.