title: Mechanisms underlying the renoprotective effect of GABA against ischemia/reperfusion-induced renal injury in rats.
abstract: The excitation of the renal sympathetic nervous system plays an important role in the development of ischemic acute kidney injury (AKI) in rats. We have reported that intravenous treatment with GABA has preventive effects on ischemia/reperfusion (I/R)-induced renal dysfunction with histological damage in rats. However, detailed mechanisms of the action of GABA on the renal injury were still unknown. Therefore, in the present study, we aimed to clarify the detailed mechanisms of GABA in ischemic AKI in rats. Ischemic AKI was induced by clamping the left renal artery and vein for 45 min. Thereafter, the kidney was reperfused to produce I/R-induced injury. Intravenous or intracerebroventricular treatment with 3-[[[(3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432), a GABA(B) receptor antagonist, abolished the suppressive effects of intravenously applied GABA on enhanced renal sympathetic nerve activity during ischemia, leading to the elimination of the renoprotective effects of GABA. Intracerebroventricular treatment with GABA or intravenous treatment with baclofen, a selective GABA(B) receptor agonist, prevented I/R-induced renal injury equivalent to intravenous treatment with GABA. However, intravenous treatment with bicuculline, a GABA(A) receptor antagonist, failed to affect the preventive effects of GABA on ischemic AKI. Therefore, we demonstrated the novel finding that the preventive effect of GABA on ischemic AKI through the suppression of enhanced renal sympathetic nerve activity induced by renal ischemia is presumably mediated via GABA(B) receptor stimulation in the central nervous system rather than peripheral GABA(B) receptor.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan. kobuchi-s@huhs.ac.jp
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kobuchi
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tanaka
authors.forename: Takuya
authors.initials: T
authors.lastname: Shintani
authors.forename: Rie
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ohkita
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ayajiki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007668:Kidney / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D010721:Phosphinic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D018080:Receptors, GABA-B / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D013564:Sympathetic Nervous System / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D018755:GABA Agonists; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C083008:CGP 52432; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D001640:Bicuculline