Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development

Background Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAI Ds) has been associated with renal dysgenesis in humans. Methods. These studies characterized cyclooxygenase-2 (COX-2) versus COX-1- selective inhibition on nephrogenesis in the rodent using histomorphometry immunohistology, and in situ hybridization. Results. Administration of a COX-2-selective inhibitor (SC58236), started d uring pregnancy until weaning, significantly impaired development of the re nal cortex and reduced glomerular diameter in both mice and rats. An identi cal phenotype was demonstrated in COX-2 -/- mice. In contrast to its effect s on the developing kidney, a COX-2 inhibitor had no effect on glomerular v olume in adult mice. This effect was specific for COX-2 because maternal ad ministration of a COX-1-selective inhibitor (SC58560) did not affect renal development despite significantly inhibiting gastric mucosal prostaglandin E-2 (PGE(2)) synthesis in pups. The expression of COX-2 immunoreactivity pe aked in the first postnatal week and was localized to S-shaped bodies and t he macula densa in the cortex. Treatment with a COX-2 inhibitor during this period (from postnatal day 0 to day 21) severely reduced glomerular diamet er, whereas treatment limited to pregnancy did not affect glomerular size. Conclusion. These data demonstrate an important role for COX-2 activity in nephrogenesis in the rodent, and define a specific time period of susceptib ility to these effects.