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 ␥-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.

Histological Study on Effect of Mesenchymal Stem Cell Therapy on Experimental Renal Injury Induced by Ischemia/Reperfusion in Male Albino Rat

“…This might represent an inflammatory response occurring as a sequelae of ischaemia and shortage of oxygen supply. Similar observations were previously reported by researchers who demonstrated the presence of hyaline exudation in the interstitial spaces as well as peritubular congestion (32). Although reperfusion is essential for the survival of ischaemic tissue, there is good evidence that reperfusion itself causes additional cellular injury "reperfusion injury", which has been attributed to the generation of reactive oxygen species (ROS), depletion of ATP, neutrophil infiltration, and membrane lipid alterations, cytoskeletal dysfunction and intracellular Ca 2+ accumulation (27).…”

GGsTop, a novel and specific γ-glutamyl transpeptidase inhibitor, protects hepatic ischemia-reperfusion injury in rats

“…GGsTop covalently binds between the side chain oxygen of Thr-381 of human GGT1 (hGGT1) and the phosphate of GGsTop, resulting in an enzyme-inhibitor complex (28). Yamamoto et al (33) reported that no abnormalities were observed in general symptoms, body weight, and amount of food intake for 2 wk after intravenous administration of GGsTop at a single dose of 30 or 100 mg/kg body wt. Only less than 4% of the compound is hydrolyzed in neutral water over a month (33).…”

Human γ-Glutamyl Transpeptidase 1

“…In a variety of diseases, GGT1 is induced and mislocalized, resulting in cleavage of substrates in serum and in interstitial fluid, thereby contributing to the disease pathology. GGT1 activity has been shown to potentiate tissue damage in ischemia-reperfusion injury, to contribute to airway hyperreactivity in asthma, to initiate the metabolism of a series of glutathione-S-drug conjugates to nephrotoxins, and to increase resistance of tumors to alkylating agents (5)(6)(7)(8)(9)(10).…”