Regulação da região promotora de genes do sistema renina-angiotensina pelas proteínas SRY e SOX3

Abstract

The renin-angiotensin system (RAS) is subject to sex-specific modulation by hormones and gene products. However, sex-differences in the balance between the vasoconstrictor/proliferative ACE (angiotensin-converting enzyme)/Ang II (angiotensin II)/AGTR1 (angiotensin II receptor, type 1) axis, and the vasodilator/anti-proliferative ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7) [angiotensin-(1-7)]/MAS1 axis are poorly known. Data in the rat have suggested that the male specific Y-chromosome gene Sry might contribute to the balance between these two axes, but why the testis-determining gene has these functions remains unknown. A combination of in silico genetic/protein comparisons, functional luciferase assays for promoters of the human RAS, and RNAseq profiling in rat were used to address if regulation of Sry on the RAS is conserved in the homologous X-chromosome gene, Sox3. Both SRY and SOX3 up-regulated the promoter of Angiotensinogen (AGT), and down-regulated the promoters of ACE2, AT2, and MAS1, likely through overlapping mechanisms. The regulation by both SRY and SOX3 on the MAS1 promoter indicates a cis regulation through multiple SOX binding sites. The Renin (REN) promoter is upregulated by SRY and down-regulated by SOX3 likely through trans and cis mechanisms respectively. Sry transcripts are found in all analyzed male rat tissues including the kidney, while Sox3 transcripts are found only in the brain and testis, suggesting that the primary tissue for renin production (kidney) can only be regulated by SRY and not SOX3. These results suggest that SRY regulation of the RAS is partially shared with its X-chromosome homolog SOX3, but SRY gained a sex-specific control in the kidney for the rate-limiting step of the RAS, potentially resulting in male specific blood pressure regulation.