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Br J Pharmacol. 2011 Jul;163(5):927-36. doi: 10.1111/j.1476-5381.2011.01313.x.

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors.

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  • 1Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.

Abstract

BACKGROUND AND PURPOSE:

Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described.

EXPERIMENTAL APPROACH:

We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21.

KEY RESULTS:

All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE(2) synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2(-/-) mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology.

CONCLUSIONS AND IMPLICATIONS:

Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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