长链非编码RNA HNF4α-AS1抑制常染色体显性多囊肾病进展的机制研究

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Long non-coding RNA (lncRNA) is closely related to hereditary diseases. We found that the antisense lncRNA HNF4α-AS1 of hepatocyte nuclear factor 4α (HNF4α) was significantly down-regulated in the kidney tissue of ADPKD patients. However, there are no function and mechanism reports about this in ADPKD so far. Functional experiments showed that overexpression HNF4α-AS1 inhibited ADPKD cell proliferation. Bioinformatics analysis showed that transcription factor HNF4α may bind HNF4α-AS1 promoter and epigenetically regulate the expression of HNF4α-AS1. Based on this, we present the hypothesis that HNF4α may epigenetically regulate the expression of HNF4α-AS1 to delay the progression of ADPKD. This study aimed to use experiments in vivo and in vitro and clinical specimens to study the molecular mechanism and the clinical significance of HNF4α-HNF4α-AS1 pathway in ADPKD. This study will provide experimental basis and clinical evidences for screening the new ADPKD markers and therapy targets.

常染色体显性多囊肾病(ADPKD)是最常见的遗传性肾病。长链非编码RNA(lncRNA)与遗传性疾病密切相关。我们发现肝细胞核因子4α(HNF4α)的反义链lncRNA HNF4α-AS1在ADPKD患者肾脏组织中显著下调，但迄今为止尚无其在ADPKD中功能及机制报道。功能实验显示过表达HNF4α-AS1可抑制ADPKD细胞增殖；生物信息学分析表明宿主基因HNF4α可能作为转录因子与HNF4α-AS1启动子结合表观调控HNF4α-AS1的表达。基于此，我们提出假说：HNF4α 可能表观调控其反义链lncRNA HNF4α-AS1抑制ADPKD进展。本项目拟采用体内外实验与临床标本研究HNF4α-AS1在ADPKD中的各项生物学功能，阐明HNF4α－HNF4α-AS1调节通路参与ADPKD进展的分子机制及其临床意义，为筛选ADPKD新型标记物和治疗靶点提供实验基础和临床依据。

常染色体显性多囊肾病(ADPKD)是最常见的遗传性肾病。长链非编码RNA(lncRNA)与遗传性疾病密切相关。我们发现肝细胞核因子4α(HNF4α)的反义链lncRNA HNF4α-AS1在ADPKD细胞、PKD大鼠及ADPKD患者肾脏组织中显著下调。功能实验显示过表达HNF4α-AS1可抑制ADPKD细胞增殖，促进凋亡，抑制细胞周期； HNF4α可能作为转录因子与HNF4α-AS1启动子结合表观调控HNF4α-AS1的表达；HNF4α-AS1表达与ADPKD患者肾脏总体积呈负相关；过表达 HNF4α-AS1可显著抑制大鼠肾脏囊肿指数、降低肾重体重比，并保护肾功能。本项目采用体内外实验与临床标本研究HNF4α-AS1在ADPKD中的各项生物学功能，阐明HNF4α－HNF4α-AS1调节通路参与ADPKD进展的分子机制及其临床意义，为筛选ADPKD新型标记物和治疗靶点提供实验基础和临床依据。