Interspecies Differences in Renal Localization of Cyclooxygenase Isoforms: Implications in Nonsteroidal Antiinflammatory Drug-Related Nephrotoxicity

Abstract

Cyclooxygenase (COX) exists in 2 related but unique isoforms: one is constitutive (COX-1) and functions in normal cell physiology, and the other is inducible (COX-2) and is expressed in response to inflammatory stimuli. Nonsteroidal antiinflammatory drugs (NSAIDs) cause renal toxicity following inhibition of renal cyclooxygenases. Humans and animals exhibit differences in susceptibility to NSAID-related renal toxicity, 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 rats, 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 differences in the localization and level of basal expression. COX-1 is expressed at high levels in the collecting ducts and renal vasculature 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 the maculae densa, thick ascending limbs, and papillary interstitial cells in rats and dogs and in glomerular podocytes and small blood vessels in monkeys and humans. COX-2 expression is markedly increased in volume-depleted rats and dogs but not monkeys. These results indicate that significant interspecies differences exist in the presence and distribution of COX isoforms, which may help explain the difference in species susceptibility to NSAID-related renal toxicity.

Effects of Long-Term Oral Administration of Ketoprofen in Clinically Healthy Beagle Dogs

“…The ketoprofen group grade was higher than that of the control group, which indicates that fecal occult blood tests may be useful for detection of gastrointestinal bleeding disorders in dogs treated with NSAIDs. Adverse renal effects of NSAIDs result primarily from the decreased synthesis of renal vasodilative PGs (PGE2 and PGI2) [1,3,19,27]. A previous study of ketoprofenassociated adverse renal effects found decreased endogenous creatinine clearance in dogs receiving ketoprofen before castration surgery [8].…”

Bradykinin Regulates Cyclooxygenase-2 in Rat Renal Thick Ascending Limb Cells

“…4,5 Immunohistochemical localization studies have detected COX-2 in the perimacula densa region and a subset of thick ascending limb (TAL) epithelial cells located in the cortex (cTAL) 6,7 and outer medulla (mTAL) 7 as well as in interstitial medullary cells. 8 COX-2 expression in the kidney under basal conditions suggests that COX-2 may have a physiological role. Expression of the COX-2 isoform is increased in the kidney during development, 9,10 adrenalectomy, 11,12 and low-salt diet 13 ; it is decreased by glucocorticoids.…”

The Interaction between Orally Administered Non-Steroidal Anti-Inflammatory Drugs and Prednisolone in Healthy Dogs

“…Kay-Mugford et al reported that MadinDarby canine kidney cells expressed both COX-1 and COX-2 [21]. Furthermore, COX-2 is sparsely expressed in the macula densa of the normal dog kidney, and up-regulation of COX-2 in the kidney and the stomach [16] has also been reported by several studies in dogs with volume or salt depletion; these results suggest that COX-2 and COX-1 have a possible role in the response that helps maintain renal function [3,22,40]. Thus, it is thought that ketoprofen inhibits mainly COX-1 in the kidney and that prednisolone may concomitantly block up-regulation of COX-2 that helps maintain renal function, which results in a decrease of RPF and GFR and causes the renal tubular injuries and hyperalbuminuria, which are early marker of renal disease in dogs [12,13,25].…”