Hepatocyte nuclear factor 4? regulates megalin expression in proximal tubular cells.

ABSTRACT: Hepatocyte nuclear factor 4? (HNF4?) is a member of the nuclear receptor superfamily and upregulates expression of many genes in the liver, pancreas, small intestine, and colon. HNF4? 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 HNF4? in PTECs have not been investigated in detail. In the present study, we aimed to identify novel HNF4? target genes that are highly expressed in PTECs. Expression of many solute carrier transporter genes was upregulated by HNF4? 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 HNF4?, and the transactivation potential of the megalin promoter was dependent on HNF4? expression. Moreover, HNF4? was found to directly bind to an HNF4? binding site near the transcription start site in the megalin gene. These results indicate that HNF4? 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.

SUBMITTER: Sasaki S 

PROVIDER: S-EPMC6295598 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature