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(2) (PLA(2)) activity. Based on these results, we tested the hypothesis that the simultaneous inhibition of PLA(2) 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;
gamma-glutamylcysteine synthetase inhibitor) and 30 microg/kg of
manoalide (PLA(2) inhibitor), following which significant elevations in serum
creatinine and urinary lysosomal
enzyme levels (elevation of
N-acetyl-beta-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(2) 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(2) and GSH depletion are necessary for the induction of
acute renal failure.