Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters.
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/ANG II/AT1 axis, and the vasodilator/antiproliferative ACE2/ANG-(1-7)/MAS axis are poorly known. Data in the rat have suggested the male-specific Y-chromosome gene Sry to contribute to 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 RNA-Seq 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 upregulated the promoter of Angiotensinogen (AGT) and downregulated the promoters of ACE2, AT2, and MAS, likely through overlapping mechanisms. The regulation by both SRY and SOX3 on the MAS promoter indicates a cis regulation through multiple SOX binding sites. The Renin (REN) promoter is upregulated by SRY and downregulated 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.
['Araujo|Fabiano C|FC|', 'Milsted|Amy|A|', 'Watanabe|Ingrid K M|IK|', 'Del Puerto|Helen L|HL|', 'Santos|Robson A S|RA|', 'Lazar|Jozef|J|', 'Reis|Fernando M|FM|', 'Prokop|Jeremy W|JW|']
D000595:Amino Acid Sequence D000808:Angiotensinogen D000818:Animals D001483:Base Sequence D001665:Binding Sites D016466:CHO Cells D017124:Conserved Sequence D006224:Cricetinae D003412:Cricetulus D005260:Female D020869:Gene Expression Profiling D005786:Gene Expression Regulation D006801:Humans D008156:Luciferases D008297:Male D008969:Molecular Sequence Data D007703:Peptidyl-Dipeptidase A D011401:Promoter Regions, Genetic D012083:Renin D012084:Renin-Angiotensin System D055748:SOXB1 Transcription Factors D012689:Sequence Homology, Nucleic Acid D051876:Sex-Determining Region Y Protein D014960:X Chromosome D014998:Y Chromosome
Sry Sox3 sex differences hypertension renin angiotensin system