Kömhoff M, Wang J L, Cheng H F, Langenbach R, McKanna J A, Harris R C, Breyer M D
Department of Medicine and Department of Cell Biology, Vanderbilt George M. O'Brien Kidney and Urologic Diseases Center, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Kidney Int. 2000 Feb;57(2):414-22. doi: 10.1046/j.1523-1755.2000.00861.x.
Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with renal dysgenesis in humans.
These studies characterized cyclooxygenase-2 (COX-2) versus COX-1-selective inhibition on nephrogenesis in the rodent using histomorphometry, immunohistology, and in situ hybridization.
Administration of a COX-2-selective inhibitor (SC58236), started during pregnancy until weaning, significantly impaired development of the renal cortex and reduced glomerular diameter in both mice and rats. An identical phenotype was demonstrated in COX-2 -/- mice. In contrast to its effects on the developing kidney, a COX-2 inhibitor had no effect on glomerular volume in adult mice. This effect was specific for COX-2 because maternal administration of a COX-1-selective inhibitor (SC58560) did not affect renal development despite significantly inhibiting gastric mucosal prostaglandin E2 (PGE2) synthesis in pups. The expression of COX-2 immunoreactivity peaked in the first postnatal week and was localized to S-shaped bodies and the macula densa in the cortex. Treatment with a COX-2 inhibitor during this period (from postnatal day 0 to day 21) severely reduced glomerular diameter, whereas treatment limited to pregnancy did not affect glomerular size.
These data demonstrate an important role for COX-2 activity in nephrogenesis in the rodent, and define a specific time period of susceptibility to these effects.
产前接触非甾体抗炎药（NSAIDs）与人类肾发育不全有关。
这些研究使用组织形态计量学、免疫组织化学和原位杂交技术，对环氧化酶-2（COX-2）与COX-1选择性抑制对啮齿动物肾发生的影响进行了表征。
在孕期开始至断奶期间给予COX-2选择性抑制剂（SC58236），显著损害了小鼠和大鼠肾皮质的发育，并减小了肾小球直径。在COX-2基因敲除小鼠中也表现出相同的表型。与对发育中肾脏的影响不同，COX-2抑制剂对成年小鼠的肾小球体积没有影响。这种作用对COX-2具有特异性，因为母体给予COX-1选择性抑制剂（SC58560）虽然显著抑制了幼崽胃黏膜前列腺素E2（PGE2）的合成，但并未影响肾脏发育。COX-2免疫反应性的表达在出生后第一周达到峰值，且定位于皮质中的S形小体和致密斑。在此期间（从出生后第0天至第21天）用COX-2抑制剂治疗会严重减小肾小球直径，而仅在孕期进行治疗则不会影响肾小球大小。
这些数据证明了COX-2活性在啮齿动物肾发生中的重要作用，并确定了对这些影响敏感的特定时间段。
