title: Relaxin in paraventricular nucleus contributes to sympathetic overdrive and hypertension via PI3K-Akt pathway.
abstract: Relaxin is recognized as an ovarian polypeptide hormone. Abundant relaxin binding sites are observed in hypothalamic paraventricular nucleus (PVN). This study was conducted to determine the roles and underlying mechanisms of relaxin in the PVN in sympathetic activation and hypertension in spontaneously hypertensive rats (SHR). Experiments were performed in normotensive Wistar-Kyoto rats (WKY) and SHR. Relaxin and its RXFP1 receptors in PVN were up-regulated in SHR. Relaxin-positive neurons existed in both parvocellular and magnocellular parts of the PVN. Presympathetic neurons and AVP neurons in the PVN expressed RXFP1, but not relaxin. Bilateral PVN microinjection of human relaxin-2 increased but anti-relaxin IgG reduced renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), plasma norepinephrine (NE) and arginine vasopressin (AVP) levels in SHR. The effects of relaxin-2 on RSNA and MAP were abolished by intravenous infusion of ganglionic blocker hexamethonium, and attenuated by AVP V1 receptor antagonist AAVP. Akt phosphorylation was enhanced in SHR, and relaxin-2 stimulated Akt phosphorylation and p85α subunit of PI3K expression. PI3K inhibitor LY294002 or Akt inhibitor MK-2206 abolished the effects of relaxin-2 on the RSNA, MAP and plasma NE, and attenuated the relaxin-2-induced AVP secretion. STAT5a and polymerase II (Pol II) binding to relaxin-promoter were significantly increased in SHR. Chronic PVN infusion of relaxin-2 with osmotic pumps in normal rats induced sympathetic activation, AVP secretion and hypertension accompanied with cardiovascular remodeling. Relaxin in the PVN contributes to sympathetic overdrive and hypertension via PI3K-Akt pathway.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Hai-Jian
authors.initials: HJ
authors.lastname: Sun
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Ye-Bo
authors.initials: YB
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Jue-Jin
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yue-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xing-Ya
authors.initials: XY
authors.lastname: Gao
authors.affiliation: Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Kang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: gqzhucn@njmu.edu.cn.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D012065:Relaxin / Q000008:administration & dosage / Q000378:metabolism*; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012065:Relaxin; C095068:RLN2 protein, human; C504789:Rxfp1 protein, rat
keywords: Hypertension; Paraventricular nucleus; Relaxin; Sympathetic; Vasopressin