Aldosterone alters the chromatin structure of the murine endothelin-1 gene

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• 作者：Amanda K. Welch^a ; ^b ; I. Jeanette Lynch^a ; ^c ; Michelle L. Gumz^c ; ^d ; Brian D. Cain^d ; Charles S. Wingo^a ; ^c ; ^{cswingo@ufl.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Aldosterone ; Chromatin structure ; Chromatin ; Epigenetics ; Kidney
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：159
• 期：Complete
• 页码：121-126
• 全文大小：815 K

文摘

Aldosterone increases sodium reabsorption in the renal collecting duct and systemic blood pressure. Paradoxically, aldosterone also induces transcription of the endothelin-1 (Edn1) gene to increase protein (ET-1) levels, which inhibits sodium reabsorption.

Aims

Here we investigated changes in the chromatin structure of the Edn1 gene of collecting duct cell lines in response to aldosterone treatment. The Edn1 gene has a CpG island that encompasses the transcription start site and four sites in the 5′ regulatory region previously linked to transcriptional regulation.

Materials and methods

The chromatin structure of the Edn1 gene was investigated using a quantitative PCR-based DNaseI hypersensitivity assay in murine hepatocyte (AML12), renal cortical collecting duct (mpkCCD_C14), outer medullary collecting duct1 (OMCD1), and inner medullary collecting duct-3 (IMCD-3) cell lines.

Key findings

The CpG island was uniformly accessible. One calcium-responsive NFAT element remained at low chromatin accessibility in all cell lines under all conditions tested. However, the second calcium responsive NFAT element located at − 1563 bp upstream became markedly more accessible in IMCD-3 cells exposed to aldosterone. Importantly, one established aldosterone hormone response element HRE at − 671 bp relative to the transcription start site was highly accessible, and another HRE (− 551 bp) became more accessible in aldosterone-treated IMCD-3 and OMCD1 cells.

Significance

The evidence supports a model in which aldosterone activation of the mineralocorticoid receptor (MR) results in the MR-hormone complex binding at HRE at − 671 bp to open chromatin structure around other regulatory elements in the Edn1 gene.