title: Preventive effect of GGsTop, a novel and selective γ-glutamyl transpeptidase inhibitor, on ischemia/reperfusion-induced renal injury in rats.
abstract: GGsTop [2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid], is a novel, highly selective, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor with no inhibitory activity on glutamine amidotransferases. In this study, we investigated the effects of treatment with GGsTop on ischemia/reperfusion-induced renal injury in uninephrectomized rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 1 day after reperfusion. Treatment with GGsTop (1 and 10 mg/kg i.v.) 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction in a dose-dependent manner. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which was significantly suppressed by the GGsTop treatment. In renal tissues exposed to ischemia/reperfusion, GGT activity was markedly increased immediately after reperfusion, whereas renal superoxide production and malondialdehyde level were significantly increased 6 h after reperfusion. These alterations were abolished by the treatment with GGsTop. In addition, renal glutathione content was decreased by the 45-min ischemia, but its level was markedly elevated by the GGsTop treatment. Our results demonstrate that the novel and highly selective GGT inhibitor GGsTop prevents ischemia/reperfusion-induced AKI. The renoprotective effect of GGsTop seems to be attributed to the suppression of oxidative stress by inhibiting GGT activation, thereby preventing the degradation of glutathione.
authors.affiliation: Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Bunta
authors.initials: B
authors.lastname: Watanabe
authors.forename: Jun
authors.initials: J
authors.lastname: Hiratake
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tanaka
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ohkita
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D000613:Aminobutyrates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis / Q000187:drug effects; D007677:Kidney Function Tests; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D058990:Molecular Targeted Therapy; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010100:Oxygen / Q000032:analysis; D020011:Protective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D013481:Superoxides / Q000032:analysis; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C569224:2-amino-4-((3-(carboxymethyl)phenyl)(methyl)phosphono)butanoic acid; D000613:Aminobutyrates; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D020011:Protective Agents; D013481:Superoxides; D008315:Malondialdehyde; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D010100:Oxygen