Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: gene expression profiles in the brain.
Spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) are frequently used as rat models not only of essential hypertension and stroke, but also of attention-deficit hyperactivity disorder (ADHD). Normotensive Wistar-Kyoto rats (WKY) are used as the control rats in these cases. An increasing number of studies has demonstrated the critical role of the central nervous system in the development and maintenance of hypertension. In a previous study, we analyzed the gene expression profiles in the adrenal glands of SHR. Thus, in this study, we analyzed gene expression profiles in the brains of SHR in order to identify the genes responsible for causing hypertension and stroke, as well as those involved in ADHD. Using genome-wide microarray technology, we examined the gene expression profiles in the brains of 3 rat strains (SHR, SHRSP and WKY) when the rats were 3 and 6 weeks of age, a period in which the rats are considered to be in a pre-hypertensive state. Gene expression profiles in the brain were compared between SHR and WKY, and between SHRSP and SHR. A total of 179 genes showing a >4- or <-4-fold change in expression were isolated, and candidate genes were selected using two different web tools: the first tool was the Database for Annotation, Visualization and Integrated Discovery (DAVID), which was used to search for significantly enriched genes, and categorized them using Gene Ontology (GO) terms, and the second was the network explorer of Ingenuity Pathway Analysis (IPA), which was used to search for interaction networks among SHR- and SHRSP-specific genes. The IPA of SHR-specific genes revealed that prostaglandin E receptor 4 (Ptger4) is one of the candidate genes responsible for causing hypertension in SHR, and that albumin (Alb) and chymase 1 (Cma1) are also responsible for causing hypertension in SHR in the presence of angiotensinogen (Agt). Similar analyses of SHRSP-specific genes revealed that the angiotensin II receptor-associated gene (Agtrap) interacts with the FBJ osteosarcoma oncogene (Fos), and with the angiotensin II receptor type-1b (Agtr1b). As Agtrap and Agtr1b not only participate in the 'uptake of norepinephrine' and 'blood pressure', but also in the 'behavior' of SHRSP at 6 weeks of age, our data demonstrate a close association between hypertension and ADHD.
Hirakata General Hospital for Developmental Disorders, Hirakata, Osaka 573-0122, Japan.
Momoko
M
Yoshida
Hirakata General Hospital for Developmental Disorders, Hirakata, Osaka 573-0122, Japan.
Yuko
Y
Watanabe
Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Kyosuke
K
Yamanishi
Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Akifumi
A
Yamashita
Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Hideyuki
H
Yamamoto
DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Daisuke
D
Okuzaki
Hirakata General Hospital for Developmental Disorders, Hirakata, Osaka 573-0122, Japan.
Kazunori
K
Shimada
DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Hiroshi
H
Nojima
Department of Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Teruo
T
Yasunaga
Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Haruki
H
Okamura
Department of Neuropsychiatry, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Hisato
H
Matsunaga
Hirakata General Hospital for Developmental Disorders, Hirakata, Osaka 573-0122, Japan.
Hiromichi
H
Yamanishi
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics; D056726:Genetic Association Studies; D006973:Hypertension / Q000235:genetics*; D058977:Molecular Sequence Annotation; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015203:Reproducibility of Results; D020521:Stroke / Q000235:genetics*