Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters

Similarities and differences of X and Y chromosome homologous genes, SRY and SOX3, in regulating the renin-angiotensin system promoters

Author Araujo, Fabiano C. Google Scholar
Milsted, Amy Google Scholar
Watanabe, Ingrid K. M. Autor UNIFESP Google Scholar
Del Puerto, Helen L. Google Scholar
Santos, Robson A. S. Google Scholar
Lazar, Jozef Google Scholar
Reis, Fernando M. Google Scholar
Prokop, Jeremy W. Google Scholar
Institution Universidade Federal de Minas Gerais (UFMG)
Univ Akron
Universidade Federal de São Paulo (UNIFESP)
Med Coll Wisconsin
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 malespecific 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.
Keywords renin angiotensin system
hypertension
Sox3
Sry
sex differences
Language English
Sponsor American Heart Association
National Institutes of Health Office of the Director
Brazilian National Institute of Science and Technology in Hormones and Women's Health
Federal University of Minas Gerais
Grant number American Heart Association: 11PRE7380033
National Institutes of Health Office of the Director: 1K01ES-025435
Date 2015-05-01
Published in Physiological Genomics. Bethesda: Amer Physiological Soc, v. 47, n. 5, p. 177-186, 2015.
ISSN 1094-8341 (Sherpa/Romeo, impact factor)
Publisher Amer Physiological Soc
Extent 177-186
Origin http://dx.doi.org/10.1152/physiolgenomics.00138.2014
Access rights Closed access
Type Article
Web of Science ID WOS:000353926600005
URI http://repositorio.unifesp.br/handle/11600/39086

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