Khan K N, Venturini C M, Bunch R T, Brassard J A, Koki A T, Morris D L, Trump B F, Maziasz T J, Alden C L
Department of Product Safety Assessment, G. D. Searle and Company, Skokie, Illinois 60077, USA.
Toxicol Pathol. 1998 Sep-Oct;26(5):612-20. doi: 10.1177/019262339802600504.
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.
环氧化酶（COX）以两种相关但独特的同工型存在：一种是组成型的（COX - 1），在正常细胞生理中发挥作用；另一种是诱导型的（COX - 2），在炎症刺激下表达。非甾体抗炎药（NSAIDs）抑制肾脏环氧化酶后会导致肾毒性。人类和动物对NSAIDs相关肾毒性的易感性存在差异，这可能与肾脏中COX一种或两种同工型表达的差异有关。在本研究中，我们评估了杂种犬、Sprague - Dawley大鼠、食蟹猴和人类肾脏中COX - 1和COX - 2的表达。此外，还研究了大鼠、犬和猴容量减少对肾脏COX表达的影响。使用以下一种或多种方法评估COX表达：逆转录聚合酶链反应、原位杂交和免疫组织化学。我们证明，在所有检测的物种的肾脏中都表达了两种COX同工型，其基础表达的定位和水平存在差异。COX - 1在所有物种的集合管和肾血管中高水平表达，在大鼠、猴和人类的少数乳头间质细胞中也有表达。大鼠和犬的致密斑、髓袢升支粗段和乳头间质细胞中存在COX - 2基础水平，猴和人类的肾小球足细胞和小血管中也有。容量减少的大鼠和犬中COX - 2表达明显增加，但猴中没有。这些结果表明，COX同工型的存在和分布存在显著的种间差异，这可能有助于解释物种对NSAIDs相关肾毒性易感性的差异。
