title: Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters.
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/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.
authors.affiliation: National Institute of Science and Technology in Molecular Medicine and Department of Obstetrics and Gynecology, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Fabiano C
authors.initials: FC
authors.lastname: Araujo
authors.affiliation: Department of Biology, The University of Akron, Akron, Ohio;
authors.forename: Amy
authors.initials: A
authors.lastname: Milsted
authors.affiliation: Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Ingrid K M
authors.initials: IK
authors.lastname: Watanabe
authors.affiliation: National Institute of Science and Technology in Molecular Medicine and Department of Obstetrics and Gynecology, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Helen L
authors.initials: HL
authors.lastname: Del Puerto
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.affiliation: National Institute of Science and Technology in Molecular Medicine and Department of Obstetrics and Gynecology, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Reis
authors.affiliation: Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin jprokop54@gmail.com.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
mesh_terms: D000595:Amino Acid Sequence; D000808:Angiotensinogen / Q000235:genetics; 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 / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011401:Promoter Regions, Genetic; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D051876:Sex-Determining Region Y Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics*; D014998:Y Chromosome / Q000235:genetics*
chemical_list: D055748:SOXB1 Transcription Factors; D051876:Sex-Determining Region Y Protein; C497747:Sry protein, rat; D000808:Angiotensinogen; D008156:Luciferases; D007703:Peptidyl-Dipeptidase A; D012083:Renin
keywords: Sox3; Sry; hypertension; renin angiotensin system; sex differences