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

• Published in: Kidney international Vol. 57; no. 2; pp. 414 - 422
• Main Authors: Kömhoff, Martin, Wang, Jun-Ling, Cheng, Hui-Fang, Langenbach, Robert, Mckanna, James A., Harris, Raymond C., Breyer, Matthew D.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-2000; Nature Publishing
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; cyclooxygenase; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - biosynthesis; Drug toxicity and drugs side effects treatment; Female; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Enzymologic - drug effects; In Situ Hybridization; Isoenzymes - genetics; Isoenzymes - metabolism; Isoenzymes - pharmacology; Kidney Cortex - embryology; Kidney Cortex - enzymology; Kidney Glomerulus - embryology; Kidney Glomerulus - enzymology; macula densa; Medical sciences; Membrane Proteins; Mice; Mice, Inbred C57BL; nephrogenesis; NSAIDs; Organic Chemicals; Pharmacology. Drug treatments; Pregnancy; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Prostaglandin-Endoperoxide Synthases - pharmacology; prostaglandins; Pyrazoles; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; Sulfonamides; Toxicity: urogenital system; nephrogenesis; cyclooxygenase; prostaglandins; macula densa; NSAIDs; Prostaglandin-endoperoxide synthase; Cyclooxygenase 2; Cyclooxygenase 1; Specificity; Female genital system; Development; Fetus; Inhibition; Mechanism of action; Kidney disease; Urinary system disease; Enzyme; Rodentia; Congenital disease; Biological activity; Non steroidal antiinflammatory agent; Pregnancy; Renal glomerulus; Vertebrata; Experimental disease; Mammalia; Mouse; Malformation; Animal; Oxidoreductases; Renal cortex
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1016/S0085-2538(15)46757-2

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