Simultaneous inhibition of renal phospholipase A(2) and glutathione synthesis by manoalide and DL-buthionine sulfoximine induces acute tubular dysfunction in rats

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 inhib ition of phospholipase A(2) (PLA(2)) activity. Based on these results, we t ested the hypothesis that the simultaneous inhibition of PLA2 and GSH synth esis induces acute renal failure similar in characteristics to gentamicin-i nduced acute renal failure. Male Sprague-Dawley rats kept under standard la boratory conditions were administered 3 mmol/kg of DL-buthionine sulfoximin e (BSO; gamma-glutamylcysteine synthetase inhibitor) and 30 mu g/kg of mano alide (PLAP inhibitor), following which significant elevations in serum cre atinine and urinary lysosomal enzyme levels (elevation of N-acetyl-beta-D-g lucosaminidase activity) were observed. The renal tissue GSH content was re duced in the group that received both BSO and manoalide as compared with th e group that received manoalide alone. The renal tissue GSH content was als o reduced in the group that received BSO alone. The renal tissue concentrat ion of 2-thiobarbituric-acid-reactive substances increased rapidly, followe d by an increase in renal tissue total phospholipid concentration in the gr oup that received both BSO and manoalide. In contrast, the activity of PLA( 2) in renal tissue decreased in the group that received both BSO and manoal ide as compared with the groups that received BSO alone or physiological sa line. In conclusion, concomitant administration of BSO and manoalide induce s renal tubular damage and acute renal failure in rats, similar in characte ristics to gentamicin-induced nephrotoxicity, whereas administration of BSO or manoalide alone did not. These results suggest that both inhibition of PLA(2) and GSH depletion are necessary for the induction of acute renal fai lure. Copyright (C) 2000 S. Karger AG,Basel.