title: Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease.
abstract: Sympathoexcitation plays an important role in the pathogenesis of hypertension in patients with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls sympathetic outflow through γ-amino butyric acid (GABA)-ergic mechanisms. Renal denervation (RDN) exerts a long-term antihypertensive effect in hypertension with CKD; however, the effects of RDN on sympathetic nerve activity and GABA-ergic modulation in the PVN are not clear. We aimed to elucidate whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD.
  
  
  
  In 5/6-nephrectomized male Institute of Cancer Research mice (Nx) at 4 weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by sympathoexcitation. The Nx-mice underwent RDN or sham operation, and the mice were divided into three groups (Control, Nx-Sham, and Nx-RDN). At 2 weeks after RDN, SBP was significantly decreased and urinary sodium excretion was increased in Nx-RDN compared with Nx-Sham. Urinary norepinephrine excretion (uNE) levels did not differ significantly between Nx-RDN and Nx-Sham. At 6 weeks after RDN, SBP continued to decrease and uNE levels also decreased in Nx-RDN compared with Nx-Sham. Bicuculline microinjection into the PVN increased mean arterial pressure and lumbar sympathetic nerve activity in all groups. The pressor responses and change in lumbar sympathetic nerve activity were significantly attenuated in Nx-Sham, but were enhanced in Nx-RDN at 6 weeks after RDN.
  
  
  
  The findings from the present study indicate that RDN has a prolonged antihypertensive effect and, at least in the late phase, decreases sympathetic nerve activity in association with enhanced GABA-ergic input into the PVN in mice with CKD.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nishihara
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Takesue
authors.affiliation: Department of Advanced Cardiovascular Regulation and Therapeutics for Cardiovascular Diseases, Kyushu University Center for Disruptive Cardiovascular Medicine, Fukuoka, Japan. Electronic address: hyoshi@cardiol.med.kyushu-u.ac.jp.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003714:Denervation; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D059330:GABAergic Neurons / Q000502:physiology*; D006830:Hydralazine / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology / Q000601:surgery; D008297:Male; D008813:Mice, Inbred ICR; D009392:Nephrectomy; D009638:Norepinephrine / Q000652:urine; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology / Q000601:surgery*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000503:physiopathology / Q000601:surgery*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D006830:Hydralazine; D009638:Norepinephrine
keywords: Chronic kidney disease; Hypertension; Paraventricular nucleus of the hypothalamus; Renal nerve denervation; Sympathetic nerve activity; γ-amino butyric acid