title: Genetic analysis of genes causing hypertension and stroke in spontaneously hypertensive rats.
abstract: Spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) are frequently used as model rats not only in studies of essential hypertension and stroke, but also in studies of attention deficit hyperactivity disorder (ADHD). Normotensive Wistar-Kyoto rats (WKY) are normally used as controls in these studies. In this study, using these rats, we aimed to identify the genes causing hypertension and stroke, as well as the genes involved in ADHD. Since adrenal gland products can directly influence cardiovascular, endocrine and sympathetic nervous system functions, gene expression profiles in the adrenal glands of the 3 rat strains were examined using genome-wide microarray technology 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 were compared between SHR and WKY and between SHRSP and SHR. A total of 353 genes showing more than a 4-fold increase or less than a 4-fold decrease in expression were isolated and candidate genes were selected as significantly enriched genes. SHR-specific genes isolated when the rats were 3 weeks of age contained 12 enriched genes related to transcriptional regulatory activity and those isolated when the rats were 6 weeks of age contained 6 enriched genes related to the regulation of blood pressure. SHRSP-specific genes isolated when the rats were 3 weeks of age contained 4 enriched genes related to the regulation of blood pressure and those isolated when the rats were 6 weeks of age contained 4 enriched genes related to the response to steroid hormone stimulus. Ingenuity pathway analysis of enriched SHR-specific genes revealed that 2 transcriptional regulators, cAMP responsive element modulator (Crem) and Fos-like antigen 1 (Fosl1), interact with blood pressure-regulating genes, such as neurotensin (Nts), apelin (Apln) and epoxide hydrolase 2, cytoplasmic (Ephx2). Similar analyses of SHRSP-specific genes revealed that angiotensinogen (Agt), one of the blood pressure-regulating genes, plays pivotal roles among SHRSP-specific genes. Moreover, genes associated with ADHD, such as low density lipoprotein receptor (Ldlr) and Crem, are discussed.
authors.affiliation: Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamanishi
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Xu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshida
authors.forename: Akifumi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Naohisa
authors.initials: N
authors.lastname: Goto
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishiguchi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shimada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
authors.forename: Teruo
authors.initials: T
authors.lastname: Yasunaga
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Hisato
authors.initials: H
authors.lastname: Matsunaga
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamanishi
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000818:Animals; D004843:Epistasis, Genetic; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000150:complications* / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications* / Q000235:genetics*