Regulation of multiple renin–angiotensin system genes by Sry

Milsted, Amy; Underwood, Adam; Dunmire, Jeff; Puerto, Helen L. Del; Martins, Almir de Sousa; Ely, Daniel; Turner, Monte E.

doi:10.1097/hjh.0b013e328332b88d

Cited by 50 publications

(63 citation statements)

References 35 publications

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“…The AP-1 transcription factor is not involved in testis determination, but is present and has been shown to be active in the promoters of angiotensinogen (Agt) and other RAS genes [21]. The consensus binding site for SRY co-localizes with OCT4.…”

Section: Potential Novel Sry Functionsmentioning

confidence: 99%

Review of the Y chromosome, Sry and hypertension

et al. 2010

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The following review examines the role of the SHR Y chromosome and specifically the Sry gene complex in hypertension and potential mechanisms that involve the sympathetic nervous system and renin angiotensin system. There are consistent gender differences in hypertension, with a greater proportion of males affected than females in most mammalian populations. Our earlier studies demonstrated that a portion of the gender differences in blood pressure (BP) in the SHR rat mapped to the SHR Y chromosome. In rats, males with the SHR Y chromosome have higher BP than females, or males with a different Y chromosome. Consistent with these results, several human population studies have confirmed a Y chromosome effect on BP. Our more recent studies focus on a transcription factor, Sry, as the locus involved in not only BP modulation but effects on other phenotypes. The Sry locus is an evolutionarily conserved locus on the mammalian Y chromosome responsible for testis determination and is a transcription factor. The Sry locus contains a highly conserved High Mobility Group (HMG) box region responsible for DNA binding. Mutations in the HMG box result in sex reversal. We have found multiple functional copies of Sry in SHR and WKY male rats. There is abundant evidence that testes determination may not be Sry’s only function as it is expressed in the brain, kidney and adrenal gland of adult males. These findings have potential implications for gender physiology research which involve, the sympathetic nervous system, renin angiotensin system, androgen receptor regulation and prostate physiology.

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Section: Potential Novel Sry Functionsmentioning

confidence: 99%

Review of the Y chromosome, Sry and hypertension

et al. 2010

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“…In the human and rodent brain, immunohistochemical studies reveal SRY expression in dopamine-abundant regions, such as the SNc, where it localizes within dopamine neurons (7,8). SRY regulates the transcription of genes encoding multiple components of dopamine machinery including tyrosine hydroxylase, aromatic acid dopa decarboxylase, dopamine D2 receptor, and monoamine oxidase A (7,8,25,26). Notably, reducing SRY mRNA levels in the SNc of male rats with antisense oligonucleotides leads to a reversible reduction in the number of dopaminergic cells, associated with motor deficits (8).…”

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confidence: 99%

Transient Neuroprotection by SRY Upregulation in Dopamine Cells Following Injury in Males

et al. 2014

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Emerging evidence suggest sex-specific regulation of dopamine neurons may underlie susceptibility of males to disorders such as Parkinson's disease (PD). In healthy male dopamine neurons, the Y-chromosome gene product, the sex-determining region on the Y chromosome (SRY) modulates dopamine biosynthesis and motor function. We investigated the regulation and function of SRY in a model of dopamine cell injury. Treatment with the dopaminergic toxin, 6-hydroxydopamine (6-OHDA), significantly elevated SRY mRNA expression (9-fold) in human male dopamine M17 cells. SRY up-regulation occurred via the p-quinone pathway, associated with a 3.5-fold increase in expression of GADD45γ, a DNA damage inducible factor gene and known SRY regulator. In turn, a signaling cascade involving GADD45γ/p38-MAPK/GATA activated the SRY promoter. Knockdown of SRY mRNA in 6-OHDA-treated M17 cells was deleterious, increasing levels of reactive oxygen species (ROS), pro-apoptotic marker PUMA mRNA, and cell injury (+25%, +32% and +34%, respectively). Conversely, ectopic over-expression of SRY in 6-OHDA-treated female SH-SY5Y cells was protective, decreasing ROS, PUMA, and cell injury (-40%, -46%, and -30%, respectively). However, the 6-OHDA-induced increase in SRY expression was diminished with higher concentrations of toxins or with chronic exposure to 6-OHDA. We conclude that SRY upregulation after dopamine cell injury is initially a protective response in males, but diminishes with gradual loss in dopamine cells. We speculate that dysregulation of SRY may contribute the susceptibility of males to PD.

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“…Harvey reported that oral estradiol intake elevated AngII level in postmenopausal women [37], and Brosnihan found that 17b-estradiol led to downregulation of kidney ACE2 and AGTR1 mRNA in ovariectomized apolipoprotein E-lacking female mice [38]. Additionally, Milsted found that the Sry gene complex on the Y chromosome of a spontaneously hypertensive rat had broad regulating functions to the RAS, including AGT and ACE2 [39]. All these gender-specific factors can have a role in regulation of RAS, and furthermore, the distinct reactions of RAS to ACEIs in different genders.…”

Section: Discussionmentioning

confidence: 99%