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Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development
M Kömhoff1, J L Wang, H F Cheng
1Department 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.
Background:
Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) 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 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.
Conclusion:
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.