Article Text

  1. K. K Arise1,
  2. K. N. Pandey1
  1. 1New Orleans, LA.


Atrial natriuretic peptide is an endogenous cardiac hormone that regulates sodium excretion, water balance, cell proliferation, and steriodogenesis; all directed towards reducing the blood pressure and blood volume. Membrane bound guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) is a major natriuretic peptide receptor that synthesizes the intracellular second messenger cGMP in response to ANP binding. The level and activity of Npr1 gene coding for NPRA receptor determines the biological effects of ANP in different tissues. The core transcriptional machinery of the TATA-less Npr1 gene, which encodes NPRA, consists of three SP1 binding sites and the inverted CCAAT box. The promoter region of Npr1 gene has been shown to contain several putative binding sites for the known transcription factors, but the functional significance of most of these cis-acting elements in Npr1 gene is yet to be elucidated. The objective of this study was to determine and characterize the functional promoter region of Npr1 gene in response to angiotensin II (AngII), which antagonizes the effect of ANP and NPRA. Here we have studied the effect of Ang II on its promoter activity and expression of Npr1 gene in cultured mouse mesangial cells. Mesangial cells were cultured and maintained in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum. Hormone treatments were carried out in cells grown in serum-free DMEM containing 0.1% bovine serum albumin (BSA). Cells were transfected using lipofectamine-2000 reagent. The promoter analysis of Npr1 gene revealed the presence of repressor elements in the regions -1841 to -916 bp relative to transcription start site. The deletion analysis showed that the promoter region approximately -1225 bp to -966 bp upstream of transcription start site contains the cis-elements involved in Ang II-mediated transcriptional repression of the Npr1 gene. The dual luciferase assay of the promoter constructs ΔA1 to ΔA6 showed inhibitory effect in the presence of Ang II and is responsible for the transcriptional repression of the Npr1 gene by Ang II. The present study reveals the presence of functional cis-regulatory elements in the promoter region of the murine Npr1 gene, which functions in response to Ang II treatment in mesangial cells. The findings of this study will be critical in further understanding the interactive roles of Ang II in the NPRA-dependent signaling pathways mediating the physiology and pathophysiology of hypertension and cardiovascular disorders.

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