Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom;
Kidney Genetics Group, Academic Unit of Nephrology, The Medical School, University of Sheffield, United Kingdom.
Am J Physiol Renal Physiol. 2017 Apr 1;312(4):F577-F588. doi: 10.1152/ajprenal.00607.2016. Epub 2017 Jan 11.
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common cause of end-stage renal disease. The disease course can be highly variable and treatment options are limited. To identify new therapeutic targets and prognostic biomarkers of disease, we conducted parallel discovery microarray profiling in normal and diseased human cystic kidney cells. A total of 1,515 genes and 5 miRNA were differentially expressed by more than twofold in cells. Functional enrichment analysis identified 30 dysregulated signaling pathways including the epidermal growth factor (EGF) receptor pathway. In this paper, we report that the EGF/ErbB family receptor ErbB4 is a major factor driving cyst growth in ADPKD. Expression of ErbB4 in vivo was increased in human ADPKD and cystic kidneys, both transcriptionally and posttranscriptionally by mir-193b-3p. Ligand-induced activation of ErbB4 drives cystic proliferation and expansion suggesting a pathogenic role in cystogenesis. Our results implicate ErbB4 activation as functionally relevant in ADPKD, both as a marker of disease activity and as a new therapeutic target in this major kidney disease.
常染色体显性多囊肾病（ADPKD）是导致终末期肾病的第四大常见病因。该疾病的病程变化多样，治疗选择有限。为了寻找新的治疗靶点和疾病预后生物标志物，我们平行进行了正常和病变人类囊性肾病细胞的发现性微阵列分析。细胞中共有 1515 个基因和 5 个 miRNA 的表达差异超过两倍。功能富集分析鉴定出 30 个失调的信号通路，包括表皮生长因子（EGF）受体通路。在本文中，我们报告称，EGF/ErbB 家族受体 ErbB4 是 ADPKD 中驱动囊肿生长的主要因素。ErbB4 在体内的表达在人 ADPKD 和囊性肾脏中增加，这是通过 mir-193b-3p 在转录和转录后水平上增加的。配体诱导的 ErbB4 激活驱动囊性增殖和扩张，表明其在囊发生中具有致病作用。我们的研究结果表明，ErbB4 的激活在 ADPKD 中具有功能相关性，既是疾病活动的标志物，也是这种主要肾脏疾病的新治疗靶点。
