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Renal Nerve Denervation Suppresses the Progression of End Organ Damage via Modulating the GABAergic Mechanisms in the Brain in Hypertensive Mice with Chronic Kidney Disease
Author(s) -
Nishihara Masaaki,
Hirooka Yoshitaka
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb642
Subject(s) - medicine , endocrinology , denervation , kidney , kidney disease , sympathetic nervous system , pathogenesis , urinary system , hypertensive nephropathy , blood pressure , diabetic nephropathy
Background Sympathoexcitation is strongly involved in the pathogenesis of hypertension accompanied with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls the sympathetic outflow through GABA‐ergic mechanisms in hypertension. The renal nerve denervation (RDN) exerts a certain long term antihypertensive effect; however the precise mechanism is not known. In the present study, we examined whether RDN reduces sympathetic outflow through GABA in the PVN and improves the end organ damage in mice with CKD. Methods and Results In 5/6‐nephrectomized ICR‐mice (Nx) at 4‐weeks after nephrectomy, systolic BP (SBP) was significantly increased (vs. Sham, 143±2 vs. 109±2mmHg, n=12–24, p<0.01), accompanied by sympathoexcitation (urinary norepinephrine (uNE): vs. Sham, 424±26 vs. 226±17μg/24hrs, n=12–24, p<0.01). Nx‐mice developed albuminuria (vs. Sham, 510±97 vs. 102±17mg/g creatinine, n=6–16, p<0.01), and echocardiographic left‐ventricular hypertrophy (LVH) (vs. Sham, 1.18±0.01 vs. 0.98±0.03mm, n=6–24, p<0.01) compared with sham‐mice. We performed RDN or sham operation and divided into 3 groups (Sham‐sham, Nx‐sham, and Nx‐RDN, n=12 for each). At 2‐weeks after RDN, SBP was significantly decreased (123±2 vs. 136±2 mmHg, n=12 for each, p<0.01), and urinary sodium excretions were increased (0.64±0.04 vs. 0.47±0.03 mmol/24hrs, n=8 for each, p<0.01) in Nx‐RDN compared with those in Nx‐sham. The uNE levels were not different between two groups. At 6‐weeks after RDN, SBP was kept decreasing (125±1 vs. 140±3 mmHg, n=12 for each, p<0.01) and uNE levels were also decreased (386±32 vs. 541±35 μg/24hrs, n=12 for each, p<0.01) in Nx‐RDN compared with those in Nx‐sham. The urinary sodium excretions were not different between two groups. Bicuculline (GABA‐A receptor antagonist, 50pmol) microinjection into PVN increased mean arterial pressure (MAP) and lumbar sympathetic nerve activity (LSNA) in all groups. The pressor responses and the change in LSNA were significantly attenuated in Nx‐sham (vs. Sham‐sham, ΔMAP/baseline MAP [%], 33±4 vs. 66±6 %; ΔLSNA (%baseline), 57±7 vs. 112±8 %, p<0.01, n=6 for each), but were enhanced in Nx‐RDN at 6‐weeks after RDN (vs. Nx‐sham, ΔMAP/baseline MAP [%], 60±6 vs. 33±4 %; ΔLSNA (%baseline), 94±5 vs. 57±7 %, p<0.05, n=6 for each). The albuminuria was suppressed (533±121 vs. 1001±192 mg/g creatinine, n=8, p<0.01), and LVH was regressed (1.08±0.02 vs. 1.24±0.03mm, n=12, p<0.05) in Nx‐RDN compared with those in Nx‐sham at 6‐weeks after RDN. The plasma aldosterone concentration (PAC) level was significantly decreased in Nx‐RDN compared with Nx‐sham (365±38 vs. 633±42pg/ml, n=12, p<0.01). Conclusion These data indicate that long term antihypertensive effect exerted by renal nerve denervation suppresses the end organ damage, at least in part, by reducing sympathetic outflow through GABA in the PVN in hypertensive mice with CKD.