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Enhanced expression of natriuretic peptide receptor‐A gene ( Npr1 ) by Ets‐1 and all‐trans retinoic acid signaling
Author(s) -
Kumar Prerna,
Bolden Gevoni,
Pandey Kailash N
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.782.4
Subject(s) - npr1 , gene knockdown , retinoic acid , transcription factor , chromatin immunoprecipitation , npr2 , microbiology and biotechnology , reporter gene , biology , transcriptional regulation , transcription (linguistics) , atrial natriuretic peptide , retinoic acid receptor , chemistry , gene expression , natriuretic peptide , promoter , gene , biochemistry , medicine , endocrinology , heart failure , linguistics , philosophy
Activation of guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) produces the second messenger cGMP, which plays a pivotal role in maintaining blood pressure and cardiovascular homeostasis. The present study was aimed at gaining insight into the function of Ets‐1 and retinoic acid signaling in the regulation of Npr1 gene transcription and expression. Npr1 promoter‐reporter deletion constructs were transiently transfected in mouse mesangial cells (MMCs) and transcriptional activity was measured by dual luciferase assay. Overexpression of Ets‐1 enhanced Npr1 promoter activity by almost 12‐fold, whereas mutagenesis of the two Ets‐1 binding sites decreased the promoter activity by 90%. Chromatin immunoprecipitation assays confirmed the in vivo binding of Ets‐1 to Npr1 promoter. All‐trans retinoic acid (ATRA) greatly enhanced Npr1 gene transcription using Ets‐1 binding sites in a dose‐dependent manner. Knockdown of Ets‐1 expression by siRNA significantly abrogated ATRA‐induced Npr1 gene transcription. ATRA also enhanced NPRA mRNA levels and ANP‐dependent intracellular accumulation of cGMP. In conclusion, Ets‐1 is an essential mediator of retinoic acid‐induced Npr1 gene transcription and expression and is likely to have important implications in the pathophysiology of hypertension and cardiovascular disorders. Supported by NIH grants HL 57531 and HL 62147.