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      Simultaneous Inhibition of Renal Phospholipase A 2 and Glutathione Synthesis by Manoalide and DL-Buthionine Sulfoximine Induces Acute Tubular Dysfunction in Rats

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          We have previously demonstrated that gentamicin-induced acute renal failure is mediated by the consumption of renal glutathione (GSH) and accumulation of oxidized phospholipids in tubular epithelial cells as a result of inhibition of phospholipase A<sub>2</sub> (PLA<sub>2</sub>) activity. Based on these results, we tested the hypothesis that the simultaneous inhibition of PLA<sub>2</sub> and GSH synthesis induces acute renal failure similar in characteristics to gentamicin-induced acute renal failure. Male Sprague-Dawley rats kept under standard laboratory conditions were administered 3 mmol/kg of DL-buthionine sulfoximine (BSO; γ-glutamylcysteine synthetase inhibitor) and 30 μg/kg of manoalide (PLA<sub>2</sub> inhibitor), following which significant elevations in serum creatinine and urinary lysosomal enzyme levels (elevation of N-acetyl-β- D-glucosaminidase activity) were observed. The renal tissue GSH content was reduced in the group that received both BSO and manoalide as compared with the group that received manoalide alone. The renal tissue GSH content was also reduced in the group that received BSO alone. The renal tissue concentration of 2-thiobarbituric-acid-reactive substances increased rapidly, followed by an increase in renal tissue total phospholipid concentration in the group that received both BSO and manoalide. In contrast, the activity of PLA<sub>2</sub> in renal tissue decreased in the group that received both BSO and manoalide as compared with the groups that received BSO alone or physiological saline. In conclusion, concomitant administration of BSO and manoalide induces renal tubular damage and acute renal failure in rats, similar in characteristics to gentamicin-induced nephrotoxicity, whereas administration of BSO or manoalide alone did not. These results suggest that both inhibition of PLA<sub>2</sub> and GSH depletion are necessary for the induction of acute renal failure.

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          Manoalide, an antibiotic sesterterpenoid from the marine sponge (polejaeff)

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            Establishment of a Hydrogen Peroxide Resistant Variant of Renal Tubular Epithelial Cells: Role of Calcium-Independent Phospholipase A2 in Cell Damage

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              Biochemical Renal Manifestations Induced by Consecutive Administration of Gentamicin in Rats

              In the present study, we investigated the generation of lipid peroxides and changes in total phospholipid levels in the kidney tissue of rats with acquired resistance to gentamicin (GM). GM resistance was induced in Sprague-Dawley male rats by subcutaneously administering each rat a dose of 80 mg/kg/day of GM for 40 consecutive days. Twelve days after the GM administration, serum urea nitrogen peaked at 35 mg/dl. The urinary creatinine excretion progressively decreased, beginning 4 days after the start of GM administration. The fractional excretion of sodium progressively increased, beginning 4 days after the start of GM administration, peaking on the 10th day. However, despite the continuation of GM administration, the urinary creatinine excretion gradually increased, and the serum urea nitrogen concentrations recovered to previous levels after 21 days. We also analyzed the relationship between the acquired resistance to GM and changes in the reduced glutathione content and glutathione peroxidase activity. Simultaneously, we investigated sequential changes in the activities of phospholipase A 2 and phospholipase C, which release peroxidized membrane phospholipids into the cytoplasm via hydrolysis, as well as the relationship between changes in the kidney tissue phospholipid composition (sphingomyelin/phosphatidylcholine ratio) and renal function. We found that (1) the kidney tissue glutathione content rapidly decreased after GM administration before subsequently increasing and being maintained at a higher level; (2) the glutathione peroxidase activity showed a persistent decrease after GM administration; (3) the kidney tissue phospholipase A 2 activity decreased after GM administration, while the phospholipase C activity exhibited a sustained increase from 21 days, and (4) the spingomyelin/phosphatidylcholine ratio decreased on the 4th day before stabilizing when acquired resistance was obtained. Based on these findings, we conclude that an increased supply of reduced glutathione and the induction of an antioxidase, substituting for glutathione peroxidase, may play a significant role in the acquisition of resistance to acute renal failure which occurs with continuous GM administration. Improved membrane fluidity, achieved by maintenance of the membrane phospholipid composition by increased phospholipase C activity, may be an additional factor contributing to the recovery of the renal function.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2000
                15 March 2000
                : 8
                : 2
                : 84-90
                1st Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
                20653 Exp Nephrol 2000;8:84–90
                © 2000 S. Karger AG, Basel

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                Figures: 3, Tables: 2, References: 26, Pages: 7
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