title: A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in BPH/2J genetically hypertensive mice.
abstract: Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.
authors.affiliation: Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. geoff.head@baker.edu.au.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Jackson
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Marques
authors.forename: Anna M D
authors.initials: AM
authors.lastname: Watson
authors.forename: Kesia
authors.initials: K
authors.lastname: Palma-Rigo
authors.forename: Thu-Phuc
authors.initials: TP
authors.lastname: Nguyen-Huu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Charchar
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015773:Enalaprilat / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010425:Pentolinium Tartrate / Q000494:pharmacology; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D035683:MicroRNAs; D018733:Nicotinic Antagonists; C529100:mirn181 microRNA, mouse; D010425:Pentolinium Tartrate; D012083:Renin; D015773:Enalaprilat
keywords: hypertension; kidney; microRNAs; renin–angiotensin system; sympathetic nervous system