title: Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats.
abstract: Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 ± 15%, n = 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 ± 5% vs. control, n = 6; tiron: 8 ± 10% vs. control, n = 5; P < 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway.
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Huber
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan;
authors.forename: Rupsa
authors.initials: R
authors.lastname: Basu
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan;
authors.forename: Cassie
authors.initials: C
authors.lastname: Cecchettini
authors.affiliation: Department of Biology, University of Massachusetts, Amherst, Massachusetts; and.
authors.forename: Adolfo E
authors.initials: AE
authors.lastname: Cuadra
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan; Biotech Research Center, Michigan Technological University, Houghton, Michigan.
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Chen
authors.affiliation: Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan; Biotech Research Center, Michigan Technological University, Houghton, Michigan zhiyings@mtu.edu.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Shan
mesh_terms: D000200:Action Potentials; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure; D002478:Cells, Cultured; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012083:Renin / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D000093342:Prorenin Receptor; D000099169:Fos-Related Antigen 1
chemical_list: D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D052247:Nitric Oxide Synthase Type II; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D012083:Renin; D018808:Transcription Factor AP-1; D000093342:Prorenin Receptor; D000099169:Fos-Related Antigen 1; C500593:Cybb protein, rat
keywords: (pro)renin receptor; paraventricular nucleus; reactive oxygen species; sympathetic nerve activity