INTERSPECIES DIFFERENCES IN RENAL LOCALIZATION OF CYCLOOXYGENASE ISOFORMS - IMPLICATIONS IN NONSTEROIDAL ANTIINFLAMMATORY DRUG-RELATED NEPHROTOXICITY

Cyclooxygenase (COX) exists in 2 related but unique isoforms: one is c onstitutive (COX-1) and functions in normal cell physiology, and the o ther is inducible (COX-2) and is expressed in response to inflammatory stimuli. Nonsteroidal antiinflammatory drugs (NSAIDs) cause renal tox icity following inhibition of renal cyclooxygenases. Humans and animal s exhibit differences in susceptibility to NSAID-related renal toxicit y, which may be associated with differences in expression of 1 or both isoforms of COX in the kidney. In this study, we evaluated COX-1 and COX-2 expression in the kidneys of mixed-breed dogs, Sprague-Dawley ra ts, cynomolgus monkeys, and humans. In addition, the effect of volume depletion on renal COX expression was investigated in rats, dogs, and monkeys. COX expression was evaluated using 1 or more of the following procedures: reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. We demonstrated that both COX isoforms are expressed in the kidneys of all species examined, with d ifferences in the localization and level of basal expression. COX-1 is expressed at high levels in the collecting ducts and renal vasculatur e of all species and in a small number of papillary interstitial cells in rats, monkeys, and humans. Basal levels of COX-2 are present in th e maculae densa, thick ascending limbs, and papillary interstitial cel ls in rats and dogs and in glomerular podocytes and small blood vessel s in monkeys and humans. COX-2 expression is markedly increased in vol ume-depleted rats and dogs but not monkeys. These results indicate tha t significant interspecies differences exist in the presence and distr ibution of COX isoforms, which may help explain the difference in spec ies susceptibility to NSAID-related renal toxicity.