Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the brain
- Authors:
- Published online on: January 22, 2014 https://doi.org/10.3892/ijmm.2014.1631
- Pages: 887-896
Abstract
Introduction
Studies have been carried out to identify genes causing hypertension using 2 strains of hypertensive rats: spontaneously hypertensive rats (SHR) and a substrain derived from SHR, stroke-prone SHR (SHRSP) (1,2). Normotensive Wistar-Kyoto rats (WKY) are normally used as the control rats (1). Since SHR and SHRSP are not only used as rat models of essential hypertension and stroke, but also as rat models of attention-deficit hyperactivity disorder (ADHD), studies using these rat models are expected to reveal genes not only related to hypertension and stroke, but also those related to ADHD (3–6). In a previous study, as the first step of this project, we investigated gene expression profiles in adrenal glands in these 3 rats strains when the rats were 3 and 6 weeks of age (7).
An increasing number of studies has demonstrated the critical role of the central nervous system in the development and maintenance of hypertension and brain ventricular enlargement, accompanied by the loss of brain tissue and weight, as well as in the volume of grey matter (8,9). In this study, as a second step in identifying genes responsible for causing hypertension and stroke, as well as those related to ADHD, we compared gene expression profiles in the brains of 3 rat strains, between SHR and WKY, and between SHRSP and SHR. When the rats were at 3 and 6 weeks of age, a period in which the rats are considered to be in a pre-hypertensive state, a total of 179 genes presenting a >4- or <-4-fold change in expression were isolated.
After classifying the 179 genes according to their expression profiles, candidate genes were selected as significantly enriched genes, and categorized with Gene Ontology (GO) terms using the Database for Annotation, Visualization and Integrated Discovery (DAVID) web tools (10,11). Subsequently, the interactions of these genes were analyzed with Ingenuity Pathway Analysis (IPA). IPA of SHR-specific genes revealed that prostaglandin E receptor 4 (Ptger4) is one of the candidate genes responsible for causing hypertension in SHR (12,13), as well as albumin (Alb) and chymase 1 (Cma1), in the presence of angiotensinogen (Agt) (14–16). Similar analyses of SHRSP-specific genes revealed that angiotensin II receptor-associated gene (Agtrap) interacts with FBJ osteosarcoma oncogene (Fos), and with angiotensin II receptor type-1B (Agtr1b) (17–19). These interactions play pivotal roles among SHRSP-specific genes, and since Agtrap and Agtr1b not only participate in the ‘uptake of norepinephrine’ and ‘blood pressure’, but also in the ‘behavior’ of 6-week-old SHRSP, the data presented in the present study reveal a close association between hypertension and ADHD.
Materials and methods
Animals, RNA extraction, microarray design, microarray analysis and microarray data analysis
The details of these procedures have been described in our previous study [Yamamoto et al (7)].
Animals
The animals used in this study, SHR/Izm, SHRSP/Izm and WKY/Izm, were provided by the Disease Model Cooperative Research Association, Kyoto, Japan. Three-week-old rats were purchased and maintained for 2 days in our animal facility and used as 3-week-old rats. Five-week-old rats were purchased and, after having been maintained for 1 week in our animal facility, were used as 6-week-old rats. All the animals were handled according to the guidelines established by the Japanese Association for Laboratory Animal Science, while all experiments involving rats were approved by the Animal Care and Use Committee of Hyogo College of Medicine on September 27, 2010.
RNA extraction
Briefly, total RNA was purified using an miRNeasy kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions.
Microarray design
Expression profiling was performed using the 4x44K whole rat genome oligo microarray version 3.0 G2519F (Agilent Technologies Inc., Santa Clara, CA, USA). Eighteen 1-color microarray-based gene analyses were performed with WKY, SHR and SHRSP at 3 and 6 weeks of age as biological triplicates. Each gene expression profile was compared between SHR and WKY, as well as between SHRSP and SHR at 3 and 6 weeks of age.
Microarray analysis
Total RNA (200 ng) was reverse-transcribed into double-stranded cDNA using AffinityScript multiple temperature reverse transcriptase, and amplified. The resulting cRNA were labeled with cyanine-3-labeled cytosine triphosphate (Perkin-Elmer, Wellesley, MA, USA) using a Low Input Quick-Amp Labeling kit (Agilent Technologies Inc.). The labeled samples were hybridized with Agilent 4x44K whole rat genome arrays (Agilent Design #028282). After washing, the slides were scanned with an Agilent Microarray Scanner (G2505C). Feature extraction software (version 10.5.1.1) was used to convert the images into gene expression data.
Microarray data analysis
Raw data were imported into Subio platform version 1.12 (Subio Inc., Aichi, Japan), and raw intensity data were normalized to the 75th percentile intensity of probes above background level (gIsWellAbove=1). SHR- and SHRSP-specific genes were defined as those showing signal ratios with a >4- or <-4-fold change in expression. Raw data were accepted in Gene Expression Omnibus (GEO, accession no. GSE41452).
Quantitative real-time polymerase chain reaction (qRT-PCR)
To validate the results obtained by microarray analysis, 6 enriched genes were randomly selected from 27 unique enriched genes, and qRT-PCR was performed under 10 different experimental conditions. Total RNA (10 ng/reaction) extracted from WKY, SHR and SHRSP, was analyzed using the One-step qPCR kit (RNA-direct SYBR-Green Real-Time PCR Master Mix; Toyobo, Tokyo, Japan). Samples were run in duplicate reactions in 96-well plates, as previously described (20). Median threshold cycle values were used to calculate the fold change (FC) values between SHR and WKY, and between the SHRSP and SHR reference samples. The FC values were normalized to GAPDH levels. The following temperature profile was used: 30 sec at 90°C and 20 min at 61°C for reverse transcription according to the manufacturer’s instructions, followed by 45 cycles at 95°C for 15 sec, 65°C for 15 sec, and 74°C for 35 sec. Statistical comparisons between microarray and qRT-PCR data were performed using Spearman’s rank correlation test.
DAVID web tool analysis
An approach to annotation enrichment analysis was performed using DAVID (http://david.abcc.ncifcrf.gov/) web tools (version 6.7, 2010) (10,11). This web-based resource provides a set of functional annotation tools for the statistical enrichment of genes classified based on GO terms. We used the GO FAT category, which filters out very broad GO terms to identify statistically enriched functional groups. The annotated gene and protein symbols are presented in italics and regular font, respectively.
IPA
IPA software (Ingenuity® Systems, http://www.ingenuity.com) was used for the functional interpretation of gene expression data obtained from microarray analyses. The network explorer of IPA was used to identify relevant interactions among SHR- and SHRSP-specific genes, and to identify the shortest literature-supported paths between genes. This web tool was also used to overlay functions and diseases, and to categorize SHR- and SHRSP-specific genes by classifying them based on the disease-related functional annotations. IPA also identified the biological functions and/or diseases in the Ingenuity Knowledge Base that were most significant to each of the category sets. The level of support for the assignment was expressed by P-values calculated using the right-tailed Fisher’s exact test.
Results
Identification and classification of SHR- and SHRSP-specific genes
Since we expected the expression levels of the candidate genes to be regulated long before the increase in blood pressure occurred, i.e., during the pre-hypertensive period, we examined the expression profiles of each probe using RNA samples prepared from brain tissue obtained from rats at 3 and 6 weeks of age, and isolated a total of 388 SHR- and SHRSP-specific probes showing a >4- or <-4-fold change in expression (Table I).
 | Table INumber and classification of SHR- and SHRSP-specific probes compared between the 2 pairs of rat strains. |
We classified 388 probes into 4 groups (G-1 to G-4) depending on the 2 rat strain pairs (SHR/WKY and SHRSP/SHR) and their age (Table I) as follows: G-1 probes were isolated when the rats were 3 weeks of age and contained 66 SHR-specific probes. These 66 probes corresponded to 42 unique genes: 14 of them showed a >4-fold increase, and 28 showed a <-4-fold decrease in expression. G-2 contained 73 SHR-specific unique genes isolated when the rats were 6 weeks of age. G-3 contained 14 SHRSP-specific unique genes isolated when the rats were 3 weeks of age. G-4 contained 50 SHRSP-specific genes isolated when the rats were 6 weeks of age. As shown in Table I, 388 probes were identified, representing 179 unique genes.
Isolation of candidate genes as significantly enriched genes
Firstly, candidate genes responsible for causing hypertension, stroke and ADHD were selected from each group as significantly enriched genes using DAVID (10,11). We isolated a total of 35 enriched genes: G-1 contained 12 enriched genes categorized with 3 GO terms, G-2 contained 10 enriched genes categorized with 2 GO terms, G-3 contained 2 enriched genes categorized with 1 GO term, and G-4 contained 11 enriched genes categorized with 3 GO terms (Table I).
These 35 enriched genes consisted of 27 unique genes (Table II). To verify the results obtained by microarray analyses, we randomly selected 6 out of the 27 genes (Table III-A), performed 10 qRT-PCR experiments (Table III-B), and compared the results with those of obtained from microarray analyses by applying Spearman’s rank correlation test. The results supported the significant correlation between qRT-PCR and microarray analyses, showing an rs value of 0.697 with a two-tailed P-value of 0.025.
Categorization of enriched genes
Enriched G-1 genes were categorized into 3 GO terms: i) GO:0051657 (maintenance of organelle location) included 2 genes: LOC501349 and Alb (Table II, G-1). Alb was also categorized into GO:0008015 (blood circulation) (Table II, G-2); ii) GO:0047760 (butyrate-CoA ligase activity) included 2 genes: acyl-CoA synthetase medium-chain family 5 and 2 (Acsm5 and Acsm2, respectively); and iii) GO:0005576 (extracellular region) included 8 genes: Cma1, vascular endothelial growth factor B (Vegfb), α-fetoprotein (LOC360919), collagen-like tail subunit of asymmetric acetylcholine-esterase (Colq), chitinase 3-like 1 (Chi3l1), α-amylase 1 (Amy1a), sparc/osteonectin (Spock2) and glycoprotein hormones α chain (Cga) (Table II, G-1).
Enriched G-2 genes were categorized into 2 GO terms: i) GO:0008015 (blood circulation) included 5 genes: Agtrap, glutamate-cysteine ligase modifier subunit (Gclm), Agtr1b, Alb, and epoxide hydrolase 2 (Ephx2); and ii) GO:0006952 (defense response) included 5 genes: C-X-C motif chemokine 3 (Cxcl3), lysozyme C type 2 (Lyc2), coagulation factor II receptor (F2r), defensin β17 (Defb17) and α-synuclein (Snca) (Table II, G-2).
Enriched G-3 genes included Agtrap and Ephx2, which were categorized into GO:0008015 (blood circulation). These 2 genes were also categorized as enriched G-2 genes (Table II, G-2). Enriched G-4 genes were categorized into 3 GO terms: i) GO:0042592 (homeostatic process) included 6 genes: similar to paired-immunoglobulin-like receptor A11 (LOC690948), heat shock 70-kDa protein 1B (Hspa1b), early growth response 2 (Egr2), leukocyte immunoglobulin-like receptor B3-like (Lilrb3l), solute carrier family 9 member 3 (Slc9a3) and Snca; ii) GO:0008015 (blood circulation) included 4 genes: Agtrap, Gclm, Agtr1b and Ephx2; and iii) GO:0048168 (regulation of neuronal synaptic plasticity) included 1 gene: activity-regulated cytoskeleton-associated protein (Arc) (Table II, G-4).
Interactions among SHR-specific genes
We found that the G-1 genes did not include most of the hypertension-related genes, and that the G-2 genes included typical hypertension-related genes, such as Agtrap, Gclm, Agtr1b and Ephx2 (Table II, G-2). As these results suggested that G-1 genes included regulatory genes that control the expression of hypertension-related G-2 genes, we searched for interaction networks between G-1 and G-2 genes, using IPA software, and identified 2 interaction networks, one between Ptf1a and Amy1a, and the other between Ptger4 and neutrophil cytosolic factor 2 (Ncf2) (Fig. 1). The former interaction was also observed among G-1 genes, and the latter was also observed among G-2 genes (Fig. 1). Of note, Ptf1a and Ptger4 were not categorized with the enriched GO terms: Ptf1a encodes a protein related to transcriptional regulation, and Ptger4 encodes a receptor related to the regulatory expression of several genes (Table IV-A). For each non-enriched gene that participated in either interaction or was self-controlled, relevant references are presented (Table IV).
Interactions among SHRSP-specific genes
Since we expected the candidate genes responsible for causing stroke in SHRSP to be included in the SHRSP-specific genes, we were interested in the interactions between the G-3 and G-4 genes (Fig. 2), and identified 2 interactions: Agtrap expression was observed in the rats at 3 and 6 weeks of age and seemed to interact with 2 genes whose expression was observed in the rats at 6 weeks of age, Agtr1b and Fos (Fig. 2). Moreover, Fos expression, observed in the rats at 6 weeks of age seemed to be self-controlled, and also showed interactions with Agtrap, Agtr1b, Gclm, Egr2, as well as with Snca via Hspa1b (Fig. 2). Of note, Fos expression in the rats at 6 weeks of age seemed to control Egr2, Ephx2 and Ncf2 expression (Fig. 2), and seemed to play a pivotal role among the genes expressed in SHRSP at 6 weeks of age.
Functions and disease-related annotations of SHR- and SHRSP-specific genes
SHR- and SHRSP-specific genes were evaluated for biological relevance using IPA, and we identified significantly enriched ‘Functions’, such as molecular transport (‘uptake of norepinephrine’), the cardiovascular system (‘blood pressure’) and ‘behavior’ (Table V).
| Table VSHR- and SHRSP-specific genes classified based on the disease-related functional annotations. |
G-1 genes included 3 SHR-specific genes involved in renal damage [Alb, cytochrome P450 2c11 (Cyp2c11), and solute carrier organic anion transporter family member 6b1 (Slco6b1)], and 5 genes involved in cellular function and maintenance [Chi3l1, Cma1, leukocyte immunoglobulin-like receptor B3 (Lilrb3), lymphocyte antigen 75 (Ly75) and Ptger4] (Table V, G-1). Some of these G-1 genes, such as Cyp2c11, Slco6b1 and Ly75, were not categorized into any of the enriched gene groups, nor into any of the groups of genes that participated in the interactions between geens (Table IV-B), and for each non-enriched gene evaluated for biological relevance, relevant references are provided. G-2 genes included 3 SHR-specific genes involved in the ‘uptake of norepinephrine’ (Agtrap, Agtr1b and Snca), and 5 genes involved with ‘blood pressure’ (Agtr1b, Agtrap, Ephx2, F2r and Ncf2) (Table V, G-2). All these G-2 genes, apart from Ncf2, were categorized using enriched GO terms (Table II, G-2).
SHRSP-specific G-3 genes not only included Agtrap, involved in the ‘uptake of norepinephrine’, but also included Agtrap and Ephx2, which were involved in ‘blood pressure’ (Table V, G-3). SHRSP-specific G-4 genes included the following: i) 4 genes involved in the ‘uptake of norepinephrine’ (Agtr1b, Agtrap, Fos and Snca); ii) 4 genes involved in ‘blood pressure’ (Agtr1b, Agtrap, Ephx2 and Ncf2); and iii) 6 genes involved in the control of ‘behavior’ (Agtr1b, Arc, Egr2, Fos, Hspa1b and Snca) (Table V, G-4). Although Fos and Ncf2 were not categorized using the enriched GO terms, the remaining SHRSP-specific genes involved in the ‘uptake of norepinephrine’, ‘blood pressure’ and/or in ‘behavior’, were categorized with the enriched GO terms, i.e., GO:0008015 (blood circulation) or GO:0042592 (homeostatic process) (Table II, G-4).
Discussion
The first aim of the current study was to identify the candidate genes responsible for causing hypertension in SHR, the second was to identify genes leading to stroke, and the third was to identify genes related to ADHD. Since juvenile SHRSP present with a significant increase in motor activity, one of the typical symptoms of ADHD, as early as 6 weeks of age (3), we expected the genes isolated from the brain tissue of rats (SHR- or SHRSP-specific genes) at 3 and 6 weeks of age to include not only those related to hypertension and stroke, but also those related to ADHD.
Interactions among SHR-specific genes, and candidate genes responsible for causing hypertension in SHR
We found that G-1 genes included regulatory genes which control the expression of hypertension-related G-2 genes. We also identified interactions between G-1 and G-2 genes: one between Ptf1a and Amy1a, and another between Ptger4 and Ncf2 (Fig. 1). The first interaction (Ptf1a and Amy1a) affects carbohydrate metabolism, since Ptf1a encodes a protein that is a component of the transcription factor complex (21,22), and Amy1a encodes an amylase isoenzyme produced by the pancreas, which catalyzes the first step in the digestion of dietary starch and glycogen. However, its role in the genesis of hypertension is not clear at present (23,24). On the other hand, the interaction between Ptger4 and Ncf2 is expected to affect blood pressure, as Ncf2 was functionally involved in ‘blood pressure’ (Table V, G-2). Ptger4 encodes a member of the G-protein coupled receptor family, and leads to the phosphorylation of glycogen synthase kinase-3, which can act as a regulatory switch for numerous signaling pathways involved in the neonatal adaptation of the circulatory system, in osteoporosis, as well as in the initiation of skin immune responses (12,13). As Ncf2 encodes a 67-kDa cytosolic subunit of the multi-protein NADPH oxidase complex, its interaction with Ptger4 has been implicated in a number of cardiovascular pathologies, such as atherosclerosis, hypertension and stroke (25).
Since these predicted interactions did not include most of the hypertension-related G-2 genes, we applied the IPA software, and suggested that G-1 and G-2 gene interactions are assisted by the presence of a gene. Agt, mutations of which are associated with susceptibility to essential hypertension, was found to aid the interactions between 2 G-1 and 4 G-2 genes (Fig. 1). These data suggest that Ptger4 is one of the candidate genes responsible for causing hypertension in SHR, and that Alb and Cma1, in the presence of Agt, also behave as candidate genes causing hypertension in SHR by interacting with hypertension-related G-2 genes, such as Ncf2, Agtr1b, Agtrap and Snca (Fig. 1).
Interactions among SHRSP-specific genes, and candidate genes responsible for causing stroke in SHRSP
Since candidate genes that cause stroke in SHRSP were expected to be included in the SHRSP-specific genes, we wished to determine the interactions between G-3 and G-4 genes (Fig. 2). IPA revealed 2 interactions: Agtrap not only interacted with Agtr1b, but also with Fos, which regulates the transcription from the RNA polymerase II promoter (Fig. 2). Moreover, Fos interacted with several other G-4 genes (Fig. 2). These results indicate that Agtrap and Fos play pivotal roles in the pathogenesis of stroke. All these interactions are expected to affect blood pressure, as Agtrap, Gclm, Agtr1b and Ephx2 were categorized by DAVID analysis into GO:0008015 (blood circulation) (Table II, G-4), and, using IPA, Agtrap, Agtr1b, Ephx2 and Ncf2 were functionally found to be involved in ‘blood pressure’ (Table V, G-4).
Genes possibly participating in the development of ADHD
Three G-2 genes were found to be involved in the ‘uptake of norepinephrine’(Agtrap, Agtr1b and Snca) (Table V, G-2). Agtrap and Agtr1b were categorized into GO:0008015 (blood circulation), and Snca was categorized into GO:0006952 (defense response) (Table II, G-2). Snca regulates the homeostasis of dopaminergic and serotonergic synapses, through the trafficking of dopamine and serotonin transporters, and plays a central role in the homeostasis of noradrenergic neurons (26,27). Accordingly, the SHR-specific G-2 genes involved in the ‘uptake of norepinephrine’ are expected not only to participate in the control of ‘blood pressure’, but also in the development of ADHD symptoms. Similarly, 4 G-4 genes, Agtrap, Agtr1b, Fos and Snca, were found to be involved in the ‘uptake of norepinephrine’ (Table V, G-4). Although Fos was not categorized using the enriched GO terms (Table IV-A), these 4 genes were expected to participate in ‘blood pressure’ control, and in the development of ADHD.
Six SHRSP-specific G-4 genes (Agtr1b, Arc, Egr2, Fos, Hspa1b and Snca), were found to be functionally involved in ‘behavior’ (Table V, G-4). Of note, 3 of these 6 genes, Agtr1b, Fos and Snca, were included among those functionally involved in the ‘uptake of norepinephrine’ (Table V, G-4). The remaining 3 genes, Arc, Egr2 and Hspa1b, functionally involved in ‘behavior’, were also expected to participate in ‘blood pressure’ control, as well as in the development of ADHD. Arc plays a critical role in the consolidation of enduring synaptic plasticity and memory storage (28), while Egr2 encodes a transcription factor with 3 tandem C2H2-type zinc fingers [since defects in this gene are associated with neurological diseases, such as Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome, it has been suggested to play a role in learning and long-term potentiation (29,30)]. Hspa1b encodes a 70-kDa heat-shock protein, which is known to promote neurodegeneration in sporadic Parkinson’s disease through its functional interaction with other Parkinson’s disease-related genes (31). All the aforementioned results suggest that not only the genes involved in the ‘uptake of norepinephrine’ but also those functionally involved in ‘behavior’ participate in the development of ADHD.
In conclusion, in this study, we analyzed the gene expression profiles in the brains of 3- and 6-week-old SHR and SHRSP, and found that the G-4 genes involved in the ‘uptake of norepinephrine’ include Agtrap, Agtr1b, Snca and Fos, and those related to ‘blood pressure’ include Agtrap, Agtr1b, Ephx2 and Ncf2 (Table V, G-4). Moreover, Agtr1b, Snca, Fos, Arc, Egr2 and Hspa1b were the genes involved in ‘behavior’ (Table V, G-4). Since Agtrap expression in SHRSP at 3 and 6 weeks of age interacted with Agtr1b (Fig. 2), these 2 genes participated not only in the ‘uptake of norepinephrine’ and ‘blood pressure’, but also in ‘behavior’. These results reveal that Agtrap and Agtr1b participate in the development of hypertension and ADHD, indicating that there is a close association between hypertension and ADHD.
Acknowledgements
We would like to thank Dr Etsuro Yamanishi, President Emeritus of Hirakata General Hospital for Developmental Disorders, and Dr Aritomo Suzuki, Professor Emeritus of Kinki University, for their constant support and encouragement, and Miss Fumie Kanazawa for her expert secretarial assistance. We also thank the National Center for Biotechnology Information, USA, and DNA Data Bank of Japan for access to the network servers.
Abbreviations:
|
ADHD |
attention-deficit hyperactivity disorder |
|
DAVID |
Database for Annotation, Visualization and Integrated Discovery |
|
FC |
fold change |
|
GEO |
Gene Expression Omnibus |
|
GO |
Gene Ontology |
|
IPA |
Ingenuity Pathway Analysis |
|
qRT-PCR |
quantitative real-time polymerase chain reaction |
|
SHR |
spontaneously hypertensive rats |
|
SHRSP |
stroke-prone SHR |
|
WKY |
normotensive Wistar-Kyoto rats |
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