Upregulation of Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene Expression by All‐trans Retinoic Acid Signaling

Abstract

Atrial natriuretic peptide (ANP) exerts its physiological effects by binding to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA), which generates the second messenger cGMP. The present study was aimed at gaining insight into the function of all‐trans retinoic acid (ATRA) in the regulation of Npr1 (coding for GC‐A/NPRA) gene transcription and expression. Npr1 gene promoter‐reporter deletion constructs were transiently transfected in cultured mouse mesangial cells (MMCs) and rat thoracic aortic smooth muscle cells (RTASMCs) and transcriptional activity was measured by dual luciferase assay. The results demonstrated that ATRA enhances Npr1 promoter activity by more than 6‐fold and induces NPRA mRNA levels in a dose‐ and time‐dependent manner. The effect of ATRA was mimicked by RA receptor agonist TTNPB, which enhanced the Npr1 gene transcription by 5‐fold. ATRA also increased Ets‐1 expression and enhanced its in vivo binding to Npr1 promoter as confirmed by chromatin immunoprecipitation assay. The results showed that ATRA significantly enhanced NPRA protein expression, its guanylyl cyclase activity, and ANP‐dependent intracellular accumulation of second messenger cGMP. The results demonstrate that retinoic acid signaling enhances Npr1 gene transcription and expression, which will have important implications in hypertension and cardiovascular regulation and prevention of high blood pressure and cardiac remodeling.