Identification of genes with altered expression in male and female Schlager hypertensive mice

Abstract

BackgroundNumerous studies have shown sex differences in the onset and severity of hypertension. Despite these sex-differences the majority of animal studies are carried out in males. This study investigated expression changes in both male and female hypertensive mouse kidneys to identify common mechanisms that may be involved in the development of hypertension.MethodsThe Schlager hypertensive mouse model (BPH/2J) and its normotensive control (BPN/3J) were used in this study. Radiotelemetry was performed on 12 to 13 week old BPH/2J and BPN/3J male and female animals. Affymetrix GeneChip Mouse Gene 1.0 ST Arrays were performed in kidney tissue from 12 week old BPH/2J and BPN/3J male and female mice (n = 6/group). Genes that were differentially expressed in both male and female datasets were validated using qPCR.ResultsSystolic arterial pressure and heart rate was significantly higher in BPH/2J mice compared with BPN/3J mice in both males and females. Microarray analysis identified 153 differentially expressed genes that were common between males and females (70 upregulated and 83 downregulated). We validated 15 genes by qPCR. Genes involved in sympathetic activity (Hdc, Cndp2), vascular ageing (Edn3), and telomere maintenance (Mcm6) were identified as being differentially expressed between BPH/2J and BPN/3J comparisons. Many of these genes also exhibited expression differences between males and females within a strain.ConclusionsThis study utilised data from both male and female animals to identify a number of genes that may be involved in the development of hypertension. We show that female data can be used to refine candidate genes and pathways, as well as highlight potential mechanisms to explain the differences in prevalence and severity of disease between men and women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0101-x) contains supplementary material, which is available to authorized users.

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

“…The chemokine receptor gene Ccr5 and the gene for arachidonic acid metabolic enzyme Cyp2j2 were also found to be differentially expressed and have been implicated in hypertension (Puig et al, 2010). A later microarray analysis of kidney tissue by Chiu and colleagues compared expression in male and female BPH/2 with male and female normotensive BPN/3 (Chiu et al, 2014). Several genes were differentially expressed and associated with hypertension.…”

“…One was angiopoietin-like 7, which may reflect increased vascular pressure in the kidney. Others were Hdc and Cndp2, which are associated with histamine metabolism and possibly sympathetic activity or inflammation (Chiu et al, 2014). A gene associated with vascular aging, Edn3 , was also differentially expressed as were the DNA maintenance genes, Mcm6 and Dna2 , which are involved in telomere length maintenance.…”

Does Telomere Shortening Precede the Onset of Hypertension in Spontaneously Hypertensive Mice?

“…The BPH/2J mice are pre-hypertensive at 4 weeks (Friese et al, 2005) and have been shown to exhibit increased blood pressure at 7 weeks of age, when compared to the normotensive controls (BPN/3J) (Schlager & Sides, 1997). We have previously shown that at 12 weeks of age, systolic blood pressure is on average 34 mmHg higher in BPH/2J male mice, compared with BPN/3J mice of the same age (Chiu et al, 2014). Radiotelemetry studies on 20-week-old males have also shown that blood pressure in BPH/2J mice is consistently high and in BPN/3J mice is consistently normal (Davern et al, 2009; Jackson et al, 2014).…”

Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction

“…To begin to understand the genes and pathways underlying hydrocephalus susceptibility, we performed a DNA microarray analysis to identify strain-specific differences in gene expression in whole brains from wild type mice and nm1054 mice lacking ciliary protein CFAP221 (previously known as PCDP1), as the phenotypic differences have been well characterized and are particularly dramatic in this line 20 , 23 . Similar approaches have been effective at identifying strain-specific candidate genes and mechanisms influencing a variety of murine phenotypes, including susceptibility to infection 30 , craniofacial defects 31 , hypertension 32 , eye pigmentation defects 33 , alcohol sensitivity 34 , cigarette smoke sensitivity 35 and social behavior 36 . We analyzed gene expression levels in brains from wild type and nm1054 mice on the B6 and 129 backgrounds and identified strain-specific expression levels for a number of genes that cluster into distinct groups based on expression profile and biological function.…”