Temporal expression of the PGE2 synthetic system in the kidney is associated with the time frame of renal developmental vulnerability to cyclooxygenase-2 inhibition

American Journal of Physiology. Renal Physiology
Stefanie FrölichRolf M Nüsing

Abstract

Pharmacological blockade of cyclooxygenase-2 (COX-2) causes impairment of kidney development. The present study was aimed at determining temporal expression pattern and activity of the PGE(2) synthetic pathway during postnatal nephrogenesis in mice and its association to the time window sensitive to COX-2 inhibition. During the first 10 days after birth, we observed transient induction of mRNA and protein for microsomal PGE synthase (mPGES)-1 between postnatal days 4 (P4) and P8, but not for mPGES-2 or cytosolic PGE synthase (cPGES). PGE(2) synthetic activity using arachidonic acid and PGH(2) as substrates and also urinary excretion of PGE(2) were enhanced during this time frame. In parallel to the PGE(2) system, COX-2 but not COX-1 expression was also transiently induced. Studying glomerulogenesis in EP receptor knockout mice revealed a reduction in glomerular size in EP1(-/-), EP2(-/-), and EP4(-/-) mice, supporting the developmental role of PGE(2). The most vulnerable time window to COX-2 inhibition by SC-236 was found closely related to the temporal expression of COX-2 and mPGES-1. The strongest effects of COX-2 inhibition were achieved following 8 days of drug administration. Similar developmental damage was caused by appl...Continue Reading

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Citations

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