Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells

Shota Sasaki,Ayami Hara,Masakiyo Sakaguchi,Masaomi Nangaku,Yusuke Inoue

doi:10.1016/j.bbrep.2018.11.010

Abstract

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.

Highlights

Hepatocyte nuclear factor 4α (HNF4α), an orphan member of nuclear receptor superfamily, is highly expressed in epithelial cells in liver, pancreas, small intestine, colon, and kidney, and HNF4α is essential for maintenance of the homeostasis in these tissues [1,2]
We investigated to identify novel HNF4α target genes that are highly expressed in proximal tubular epithelial cells (PTECs) by overexpression of HNF4α in human HK-2 cells that express many characteristics of PTECs [21]
By overexpression of HNF4α in human PTEC-derived HK-2 cells, we investigated whether HNF4α has a potential to induce the expression of proximal tubule-enriched genes

Summary

Introduction

Hepatocyte nuclear factor 4α (HNF4α), an orphan member of nuclear receptor superfamily, is highly expressed in epithelial cells in liver, pancreas, small intestine, colon, and kidney, and HNF4α is essential for maintenance of the homeostasis in these tissues [1,2]. HNF4α binds to approximately 40% of the promoter region of the genes expressed in human hepatocytes and pancreatic islets [3], indicating that HNF4α is a strong regulator in the liver and pancreatic. Since Hnf4a null-mice results in embryonic lethality [4], tissue-specific Hnf4a-null mice were generated in hepatocytes, pancreatic β cells, and intestinal epithelial cells. Based on many studies using liver-specific Hnf4a-null mice, hepatic HNF4α was found to be a central regulator for hepatocyte differentiation and function though direct regulation of many liver-specific genes [5,6,7,8,9]. Mutations in HNF4α gene related to maturity-onset diabetes of the young 1 (MODY1) [11], suggesting that pancreatic β cell-specific

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