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

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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 PGE2 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). PGE2 synthetic activity using arachidonic acid and PGH2 as substrates and also urinary excretion of PGE2 were enhanced during this time frame. In parallel to the PGE2 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 PGE2. 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 application of rofecoxib, but not by the COX-1-selective inhibitor SC-560. COX-2 inhibition starting after P10 has had no effect on the size of glomeruli or on the relative number of superficial glomeruli; however, growth of the renal cortex was significantly diminished, indicating the requirement of COX-2 activity after P10. Effects of COX-2 inhibition on renal cell differentiation and on renal fibrosis needed a prolonged time of exposition of at least 10 days. In conclusion, temporal expression of the PGE2 synthetic system coincides with the most vulnerable age interval for the induction of irreversible renal abnormalities. We assume that mPGES-1 is coregulated with COX-2 for PGE2 synthesis to orchestrate postnatal kidney development and growth.

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