title: Simultaneous inhibition of renal phospholipase A(2) and glutathione synthesis by manoalide and DL-buthionine sulfoximine induces acute tubular dysfunction in rats.
abstract: 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.
authors.affiliation: 1st Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Soejima
authors.forename: S
authors.initials: S
authors.lastname: Ishizuka
authors.forename: N
authors.initials: N
authors.lastname: Miyake
authors.forename: K
authors.initials: K
authors.lastname: Fukuoka
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Kamiya
authors.forename: T
authors.initials: T
authors.lastname: Nagasawa
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000096:biosynthesis*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining; D013729:Terpenes / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D004791:Enzyme Inhibitors; D010743:Phospholipids; D013729:Terpenes; D017392:Thiobarbituric Acid Reactive Substances; D019328:Buthionine Sulfoximine; D003404:Creatinine; C045673:manoalide; D010741:Phospholipases A; D000118:Acetylglucosaminidase; D005978:Glutathione