Elsevier

Steroids

Volume 75, Issue 11, November 2010, Pages 747-753
Steroids

Review
Review of the Y chromosome, Sry and hypertension

https://doi.org/10.1016/j.steroids.2009.10.015Get rights and content

Abstract

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 involves, the sympathetic nervous system, renin–angiotensin system, androgen receptor regulation and prostate physiology.

Introduction

It has been 9 years since our group reviewed the progress on the Y chromosome and hypertension and 18 years since our original observation of a Y chromosome effect on blood pressure in SHR. This review will cover the following topics: Sry general background, potential Sry functions, Sry copies, Sry expression, Sry protein, and a comparison of Sry phenotypes. The genetic background of the Y chromosome, the development of our animal model, the effects of the Y chromosome on blood pressure phenotypes and the relationship to human studies were described in our first review [1].

There are gender differences in human hypertension, with males affected at an earlier age than females, however, the prevalence is actually higher in age adjusted females and the current rise in hypertension prevalence is primarily driven by women [2], [3]. Our original studies demonstrated that in the SHR rat a portion of the gender differences in blood pressure (BP) mapped to the SHR Y chromosome [4]. Males with the SHR Y chromosome have higher blood pressure than females, or males with a different Y chromosome. Consistent with our findings, several human population studies have confirmed the Y chromosome effect on blood pressure [5], [6]. Our more recent studies focus on a Y chromosome specific locus, Sry, as the locus involved in not only BP modulation but effects on other phenotypes. These findings have potential implications for gender physiology research involving the sympathetic nervous system, renin–angiotensin system, androgen receptor regulation and prostate physiology.

With regard to females, since hypertension prevalence in women is increasing, the mechanisms are not going to be the identical as in males with an Sry gene. The triggers for gene and physiological system activation like the RAS, SNS and oxidative stress pathways are most likely going to be regulated differently in females than in the males. Of the potential multiple genes involved in hypertension Sry is only one and females still have all the autosomal genes and potentially X-linked genes that may be involved in both protecting and facilitating hypertension.

Section snippets

Sry background

The Sry locus (sex determining region of the Y chromosome) is an evolutionarily conserved locus on the mammalian Y chromosome responsible for testis determination. Sry is a transcription factor responsible for the developmental switch in the embryonic genital ridge to testis determination in males. The Sry locus contains a highly conserved High Mobility Group (HMG) box region responsible for DNA binding, while other regions of the locus show little if any conservation [7]. Mutations in the HMG

Potential novel Sry functions

Besides the initial observation of testes determination, Sry appears to have a role in regulation of many genes which are involved in behavior, androgen receptor function, sympathetic nervous system function and the renin–angiotensin system (RAS).

We have demonstrated the interaction of Sry with tyrosine hydroxylase and increased BP following exogenous Sry expression in normotensive WKY rats [9]. Dewing et al. demonstrated that delivering Sry antisense oligonucleotides to the rat substantia

Multiple copies of Sry loci in Rattus norvegicus (Table 1)

A unique characteristic of the rat Sry complex is that there are multiple Sry loci on a single Y chromosome. The Sry gene complex from a single R. norvegicus Y chromosome from the spontaneously hypertensive rat strain (SHR/Akr) have been sequenced and analyzed for homology among copies [26]. The analysis of these sequences identified seven different Sry loci on the Y chromosome (Sry1, Sry2, Sry3, Sry3A, Sry3BI, Sry3B and Sry3C). These are paralogous copies consistent with a single phylogeny and

Human Sry

Whether Sry and the presence of multiple copies of Sry have human relevance, remains unknown as a research question. Two recent studies reported copy number variation of the SRY genes in human males, with as many as 16 copies present in some individuals in a population exposed to background radiation [27], [28]. Whether multiple human SRY copies are functional remains to be determined. The presence of multiple copies in humans lends support to our studies of the function of the multiple rat Sry

Sry transcript expression

Using a fragment analysis procedure with cDNA samples from SHR/y testis and SHR/y adrenal gland allow the identification of which specific Sry loci are expressed. Their proportions and expression patterns were significantly different in the testis and adrenal gland [26]. We have evidence that each locus is expressed. Some loci (Sry1, Sry2, Sry3 (3A) and Sry3C) are expressed in multiple tissues and in proportions that are greater than 25% of the total Sry transcripts in some tissues. The other

The Sry protein

Sry (sex-determining region of the Y chromosome), is an intronless gene that encodes a protein with a highly conserved 79–80 aa High Mobility Group (HMG) box DNA binding domain Sry shares homology with members of the HMG-1/HMG-2 protein families [29]. In vitro Sry interacts with DNA in a sequence specific manner with a high binding affinity (Kd ∼ 10−9 to 10−10 nM) [30]. Sry–DNA interactions occur at the minor groove rather than the major groove, thus it is likely that this interaction would

Renin–angiotensin system genes

The renin–angiotensin system consists of both the classical form in the circulatory system and local tissue RASs. To have a significant effect on the RAS, an effective regulator of expression of RAS genes would affect more than one gene. For example, a small effect on the angiotensinogen (Agt) gene alone might not be sufficient to shift the RAS from generating predominately vasoconstrictors to vasodilators. Because of multiple overlapping compensatory systems to maintain BP, a subtle change in

Delivery protocol for exogenous Sry electroporation to target tissues

In order to determine potential function of Sry loci in tissues that may have blood pressure regulation ability, experiments were designed to deliver exogenous Sry to adrenal gland and kidney. Either Sry1/pcDNA3.1(−), Sry2, Sry3 or control pcDNA3.1(−) vector without Sry sequences were electroporated into the left kidney medulla or adrenal medulla of adult male WKY rats under anesthetic [24], [25]. Sry transcripts from the plasmid, cannot be distinguished from endogenous Sry, therefore the use

Sry1 and SNS activation: kidney effects

In order to explore the mechanism of the BP elevation based on our earlier observations, we measured indices of the SNS – plasma catecholamines, tissue catecholamines and markers of the renin–angiotensin system – plasma renin, tissue angiotensin II, renin and ACE. There was a significant increase in telemetered BP (15–20 mmHg) after Sry1 delivery compared to control vector at days 7–21 which was normalized after 28 days [25]. When Sry2 was delivered to the kidney in the same manner there was no

Sry3 and renin–angiotensin system activation: kidney effects (Fig. 2)

After testing the effects of Sry1 and Sry2 we studied Sry3 effects on the kidney. Sry3 significantly raised telemetered BP compared to controls about 10 mmHg after 7 and 14 days and about 20 mmHg after 21 days with BP normalization at 28 days [60]. Sry3 did not significantly elevate BP in response to air stress compared to controls, whereas Sry1 did [60]. The acute pressor response to air stress supports the idea that when Sry1 was exogenously delivered there was a rapid pressor response

Sry1 and Sry3 adrenal effects

Similar to our kidney experiments we examined the effects of Sry electroporation into the adrenal medulla. We tested Sry1 and Sry3 but have not studied Sry2. There was a significant increase in BP (30 mmHg) 3 weeks after Sry1 delivery to the adrenal medulla as compared to control vector [24]. Tyrosine hydroxylase was significantly increased compared to the vector control (48 and 57%, respectively). With regard to Sry1 effects on adrenal catecholamine content there were no significant differences

Summary and conclusions

Our earlier studies showed that males with the SHR Y chromosome had elevated indices of SNS activity and BP was elevated [61]. Focusing on Sry as the Y chromosome locus showed that specifically Sry1 given exogenously to the kidney or adrenal gland elevated BP and SNS markers [24], [25]. When Sry2 was delivered to the kidney BP was not affected. However, when Sry3 was delivered to the kidney the renin–angiotensin system was activated along with sodium retention and BP elevation but SNS markers

Acknowledgements

The authors are grateful for grant support from: NIH (RO1-HL71579-01A3), Department of Biology and the Ohio Board of Regents. We appreciate the help of Emily Njus, Bob Zickelfoose, Larry Shirkey and Danny Elliott for animal care and welfare.

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    Current address: Department of Biology, Walsh University, 2020 E Maple St., North Canton, OH 44720-3336, United States.

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