title: Kynureninase is a novel candidate gene for hypertension in spontaneously hypertensive rats.
abstract: The rostral ventrolateral medulla (RVLM) plays a critical role in the tonic and reflexive regulation of arterial blood pressure. Recent studies have demonstrated that injection of kynurenic acid (KYN) into the RVLM of spontaneously hypertensive rats (SHR) decreases arterial blood pressure. We hypothesized that a relative increase in the excitatory amino acid-mediated drive of RVLM vasomotor neurons in SHR may be due to derangement of one of the enzymes that affect the KYN level in the brain. We selected kynureninase, kynureninase hydroxylase, kynurenine aminotransferase type I, and kynurenine aminotransferase type II as candidates that may affect the KYN level in the brainstem. We conducted association studies between polymorphisms of these genes and blood pressure in an F2 population derived from SHR and Wistar-Kyoto rats (WKY). The cosegregation analysis indicated that only the kynureninase gene (KYNU) polymorphism influenced systolic blood pressure (SBP) and residuals of systolic blood pressure after adjusting for heart rate and body weight (RSBP). KYNU was found to be located on rat chromosome 3, and quantitative trait loci analysis at this locus indicated that the logarithms of the odds scores for KYNU in terms of SBP and RSBP were 2.0 and 3.3, respectively. This association with blood pressure decreased in proportion to the distance from KYNU. The expression level of KYNU mRNA in the brainstem was about 3.1 and 2.9 times higher in 10-week-old and 16-week-old SHR than in age-matched WKY, respectively. The increased expression of KYNU in SHR is thought to decrease the KYN level. KYNU seems to be one of the genes that contributes to hypertension in SHR.
authors.affiliation: Research Institute, National Cardiovascular Center, Suita, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Mizutani
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tanabe
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tsujita
authors.forename: Naomi
authors.initials: N
authors.lastname: Tago
authors.forename: Naoharu
authors.initials: N
authors.lastname: Iwai
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D002874:Chromosome Mapping; D006867:Hydrolases / Q000235:genetics*; D006973:Hypertension / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics* / Q000254:growth & development; D011921:Rats, Inbred WKY
chemical_list: D012333:RNA, Messenger; D006867:Hydrolases; C021480:kynureninase