Sasaki Shota, Hara Ayami, Sakaguchi Masakiyo, Nangaku Masaomi, Inoue Yusuke
Division of Molecular Science, Graduate School of Science and Technology, Gunma University, Kiryu, Gunma 376-8515, Japan.
Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Biochem Biophys Rep. 2018 Dec 12;17:87-92. doi: 10.1016/j.bbrep.2018.11.010. eCollection 2019 Mar.
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 (), 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.
肝细胞核因子4α（HNF4α）是核受体超家族的成员，可上调肝脏、胰腺、小肠和结肠中许多基因的表达。HNF4α在肾脏的近端肾小管上皮细胞（PTECs）中也高度表达。PTECs通过转运蛋白、离子通道和受体重吸收各种物质，但尚未对PTECs中HNF4α的靶基因进行详细研究。在本研究中，我们旨在鉴定在PTECs中高表达的新型HNF4α靶基因。在人PTEC来源的HK-2细胞中，许多溶质载体转运蛋白基因的表达被HNF4α上调。值得注意的是，巨膜蛋白（）的表达，一种参与慢性肾脏病（CKD）发生和发展的各种分子的内吞受体，被HNF4α强烈诱导，并且巨膜蛋白启动子的反式激活潜能依赖于HNF4α的表达。此外，发现HNF4α直接结合到巨膜蛋白基因转录起始位点附近的HNF4α结合位点。这些结果表明，HNF4α通过在转录水平上正向调节几种溶质载体转运蛋白和巨膜蛋白基因，在维持PTECs的重吸收和代谢中发挥重要作用。
