Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells.
Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells.
复制标题
肝细胞核因子 4α 调节近端肾小管细胞中巨蛋白的表达。
DOI：
10.1016/j.bbrep.2018.11.010
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Inoue Y.
中科院分区：
文献类型：
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作者：
Sasaki S;Hara A;Sakaguchi M;Nangaku M;Inoue Y.
肝细胞核因子4α（HNF 4 α）是核受体超家族成员之一，可上调肝脏、胰腺、小肠和结肠中多种基因的表达。HNF 4 α在肾脏近端肾小管上皮细胞（PTECs）中也有高表达。PTECs通过转运蛋白、离子通道和受体重吸收各种物质，但PTECs中HNF 4 α的靶基因尚未详细研究。在本研究中，我们的目的是确定新的HNF 4 α靶基因，在PTECs中高度表达。HNF 4 α可上调人肾小管上皮细胞HK-2中多种溶质载体转运蛋白基因的表达。值得注意的是，巨蛋白（LRP 2）的表达，参与慢性肾脏疾病（CKD）的发展和进展的各种分子的内吞受体，强烈诱导HNF 4 α，巨蛋白启动子的反式激活潜力是依赖于HNF 4 α的表达。此外，发现HNF 4 α直接结合到megalin基因中转录起始位点附近的HNF 4 α结合位点。这些结果表明，HNF 4 α通过在转录水平上对溶质载体转运蛋白和megalin基因的正调控，在维持PTECs重吸收和代谢中发挥重要作用。
Hepatocyte nuclear factor 4α (HNF4α) is a member of the nuclear receptor superfamily and upregulates expression of many genes in the liver, pancreas, small intestine, and colon. HNF4α is also highly expressed in proximal tubular epithelial cells (PTECs) in kidney. PTECs reabsorb various substances through transporters, ion channels, and receptors, but the target genes for HNF4α in PTECs have not been investigated in detail. In the present study, we aimed to identify novel HNF4α target genes that are highly expressed in PTECs. Expression of many solute carrier transporter genes was upregulated by HNF4α in human PTEC-derived HK-2 cells. Notably, expression of megalin (LRP2), an endocytic receptor of various molecules involved in development and progression of chronic kidney disease (CKD), was strongly induced by HNF4α, and the transactivation potential of the megalin promoter was dependent on HNF4α expression. Moreover, HNF4α was found to directly bind to an HNF4α binding site near the transcription start site in the megalin gene. These results indicate that HNF4α plays an important role in maintaining reabsorption and metabolism in PTECs by positive regulation of several solute carrier transporter and megalin genes at the transcriptional level.