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

K├Âmhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, Breyer MD
Kidney Int. 2000 57 (2): 414-22

PMID: 10652018 · DOI:10.1046/j.1523-1755.2000.00861.x

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.

MeSH Terms (26)

Animals Anti-Inflammatory Agents, Non-Steroidal Cyclooxygenase 1 Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Dinoprostone Female Gastric Mucosa Gene Expression Regulation, Developmental Gene Expression Regulation, Enzymologic In Situ Hybridization Isoenzymes Kidney Cortex Kidney Glomerulus Membrane Proteins Mice Mice, Inbred C57BL Organic Chemicals Pregnancy Prostaglandin-Endoperoxide Synthases Pyrazoles Rats Rats, Sprague-Dawley RNA, Messenger Sulfonamides

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