Regulation of multiple renin-angiotensin system genes by Sry.
OBJECTIVE
We demonstrated that the Sry gene complex on the spontaneously hypertensive rat (SHR) Y chromosome is a candidate locus for hypertension that accounts for the SHR Y chromosome blood pressure effect. All rat strains examined to date share six Sry loci, and a seventh Sry locus (Sry3) appears to be unique to SHR male rats. Previously, we showed that Sry1 increased activity of the tyrosine hydroxylase promoter in transfected PC12 cells, and Sry1 delivered to adrenal gland of Wistar-Kyoto (WKY) rats increased blood pressure and sympathetic nervous system activity. The objective of this study was to determine whether renin-angiotensin system genes participate in Sry-mediated effects.


METHODS
Sry expression vectors were co-transfected into CHO cells with luciferase reporter constructs containing promoters of angiotensinogen (Agt -1430/+22), renin (Ren -1050/-1), angiotensin-converting enzyme (ACE) (ACE -1677/+21) and ACE2 (ACE2 -1091/+83).


RESULTS
Sry1, Sry2 and Sry3 differentially upregulated activity of the promoters of angiotensinogen, renin and ACE genes and downregulated ACE2 promoter activity. The largest effect was seen with Sry3, which increased activity of angiotensinogen promoter by 1.7-fold, renin promoter by 1.3-fold, ACE promoter by 2.6-fold and decreased activity of ACE2 promoter by 0.5-fold. The effect of Sry1 on promoter activity was significantly less than that of Sry3. Sry2 activated promoters at a significantly lower level than Sry1 did. The result of either an additive effect of Sry regulation of multiple genes in the renin-angiotensin system or alterations in expression of a single gene could favor increased levels of Ang II and decreased levels of Ang-(1-7).


CONCLUSIONS
These actions of Sry could result in increased blood pressure in males and contribute to sex differences in blood pressure.
Milsted
Amy
A
Department of Biology and Program in Integrated Bioscience, University of Akron, Akron, Ohio 44325-3908, USA. milsted@uakron.edu
Underwood
Adam C
AC
Dunmire
Jeff
J
DelPuerto
Helen L
HL
Martins
Almir S
AS
Ely
Daniel L
DL
Turner
Monte E
ME
D000085962:Angiotensin-Converting Enzyme 2; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D024282:Genes, sry; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY / Q000235:genetics*; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014998:Y Chromosome / Q000235:genetics
D051876:Sex-Determining Region Y Protein; C497747:Sry protein, rat; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin