Kobuchi Shuhei, Tanaka Ryosuke, Shintani Takuya, Suzuki Rie, Tsutsui Hidenobu, Ohkita Mamoru, Matsumura Yasuo, Ayajiki Kazuhide
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.
Clin Exp Pharmacol Physiol. 2015 Mar;42(3):278-86. doi: 10.1111/1440-1681.12350.
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.
肾交感神经系统的兴奋对大鼠缺血性急性肾损伤（AKI）的发生发展至关重要。我们曾报道，静脉注射γ-氨基丁酸（GABA）对大鼠缺血/再灌注（I/R）诱导的肾功能障碍及组织学损伤具有预防作用；然而，这些对肾损伤的作用机制仍不清楚。因此，本研究的目的是阐明GABA对大鼠缺血性AKI的作用机制。通过夹闭大鼠左肾动脉和静脉45分钟，然后再灌注肾脏以产生I/R诱导的损伤，从而诱导大鼠发生缺血性AKI。用GABAB受体拮抗剂CGP52432（100 nmol/kg，静脉注射，或1 nmol/kg，脑室内注射）处理可消除静脉注射50 μmol/kg GABA对缺血期间增强的肾交感神经活动（RSNA）的抑制作用，导致GABA的肾保护作用消失。脑室内注射0.5 μmol/kg GABA或静脉注射1 μmol/kg巴氯芬（一种选择性GABAB受体激动剂）可预防I/R诱导的肾损伤，其效果与静脉注射GABA相当。相反，静脉注射10 μmol/kg荷包牡丹碱（一种GABAA受体拮抗剂）未能影响GABA对缺血性AKI的预防作用。因此，我们得出结论，中枢神经系统中的GABAB受体刺激而非外周GABAB受体刺激，通过抑制肾缺血诱导的增强的RSNA来介导GABA对缺血性AKI的预防作用。
