title: Mechanisms underlying the renoprotective effect of GABA against ischaemia/reperfusion-induced renal injury in rats.
abstract: Excitation of the renal sympathetic nervous system is important for the development of ischaemic acute kidney injury (AKI) in rats. We reported that intravenous treatment with GABA has preventive effects against ischaemia/reperfusion (I/R)-induced renal dysfunction with histological damage in rats; however, the mechanisms underlying these effects on renal injury remain unknown. Thus, the aim of the present study was to clarify how GABA mechanistically affects ischaemic AKI in rats. Ischaemic AKI was induced in rats by clamping the left renal artery and vein for 45 min and then reperfusing the kidney to produce I/R-induced injury. Treatment with the GABAB receptor antagonist CGP52432 (100 nmol/kg, i.v., or 1 nmol/kg, i.c.v.) abolished the suppressive effects of 50 μmol/kg, i.v., GABA on enhanced renal sympathetic nerve activity (RSNA) during ischaemia, leading to elimination of the renoprotective effects of GABA. Intracerebroventricular treatment with 0.5 μmol/kg GABA or i.v. treatment with 1 μmol/kg baclofen, a selective GABAB receptor agonist, prevented the I/R-induced renal injury equivalent to i.v. treatment with GABA. Conversely, i.v. treatment with 10 μmol/kg bicuculline, a GABAA receptor antagonist, failed to affect the preventive effects of GABA against ischaemic AKI. We therefore concluded that GABAB receptor stimulation in the central nervous system, rather than peripheral GABAB receptor stimulation, mediates the preventive effect of GABA against ischaemic AKI by suppressing the enhanced RSNA induced by renal ischaemia.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan; Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
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: Yasuo
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ayajiki
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010721:Phosphinic Acids / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D058787:GABA-A Receptor Antagonists; D010721:Phosphinic Acids; D011963:Receptors, GABA-A; C083008:CGP 52432; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline
keywords: GABA; acute kidney injury; ischaemia/reperfusion; renal sympathetic nerve activity