Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis

Physiol Genomics. 2007 Jun 19;30(1):26-34. doi: 10.1152/physiolgenomics.00187.2006. Epub 2007 Feb 27.

Abstract

Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled to respond to extracellular stimuli. We studied transcription regulatory genes modulated by angiotensin II, one of the most important regulators of adrenal cortical cell function, and their role in adrenal steroidogenesis in H295R human adrenocortical cells. Angiotensin II-modulated transcription regulatory genes were identified with high-density oligonucleotide microarrays and the results validated by real-time RT-PCR. Cotransfection reporter assays were performed in H295R cells to analyze the role of these transcription regulatory genes in the control of the expression of 11beta-hydroxylase and aldosterone synthase, the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, respectively. We selected a subset of the most regulated genes for reporter plasmid studies to determine the effect on these enzymes. BHLHB2, BTG2, and SALL1 decreased expression of both enzymes, whereas CITED2, EGR2, ELL2, FOS, FOSB, HDAC5, MAFF, MITF, NFIL3, NR4A1, NR4A2, NR4A3, PER1, and VDR increased expression for both enzymes. By the ratio of aldosterone synthase to 11beta-hydroxylase expression, NFIL3, NR4A1, NR4A2, and NR4A3 show the greatest selectivity toward upregulating expression of the mineralocorticoid biosynthetic pathway preferentially. In summary, this study reports for the first time a set of transcription regulatory genes that are modulated by angiotensin II and their role in adrenal gland steroidogenesis. Abnormal regulation of the mineralocorticoid or glucocorticoid biosynthesis pathways is involved in several pathophysiological conditions; hence the modulated transcription regulatory genes described may correlate with adrenal steroidogenesis pathologies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenal Cortex / cytology
  • Adrenal Cortex / drug effects
  • Adrenal Cortex / metabolism*
  • Angiotensin II / pharmacology*
  • Cells, Cultured
  • Cytochrome P-450 CYP11B2 / genetics
  • Cytochrome P-450 CYP11B2 / metabolism
  • Gene Expression Regulation / drug effects
  • Genes, Regulator / genetics*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Plasmids / genetics
  • Promoter Regions, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Steroid 11-beta-Hydroxylase / genetics
  • Steroid 11-beta-Hydroxylase / metabolism
  • Steroids / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • Steroids
  • Angiotensin II
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase