TYPE-1 ANGIOTENSIN-II RECEPTORS OF ADRENAL-TUMORS

The present study was designed to clarify the transcriptional regulation of the human type I angiotensin II receptor (An) gene and its pathophysiological roles in steroidogenesis by adrenal tumors. A cDNA encoding type I angiotensin II receptor (ATI) was isolated from a human liver cDNA library encoding a protein of 359 amino acids with seven transmembrane segments. It is very likely that human has only one type of AT1 receptor, in contrast with rodents. A genomic clone containing 217 bp of exon 1 and 2558 bp of the 5'-flanking region of human An receptor gene was isolated. Its proximal promoter region contained putative TATA and GC boxes, CRE and API sites. Aldosterone-producing adenoma (APA) contained significantly higher levels of mRNA for An and ACTH receptors than normal tissues adjacent to APA. There were no mutations within the cytoplasmic third loops of An and ACTH receptors in APAs examined. APA showed increased expression of the mRNA for P450c11 and decreased expression of the mRNA for P450c17. These results suggest that renin-independent overproduction and clinically observed ACTH-dependent production of aldosterone in APAs may result from the enhanced transcription of P450c11 and ACTH receptor genes. The mechanism of the discordantly increased expression of AT1 receptor in APA remains to be clarified.