Abstract

Cyclooxygenase-2 (COX-2) enzyme was described as an inducible by proinflammatory cytokines whose expression is inhibited by glucocorticoids, and therefore responsible for inflammation, pain and fever. This paradigm led to development of selective inhibitors of COX-2 with the promise that they would not have adverse effects. This paradigm was challenged by the discovery of COX-2 in renal tubular cells in normal kidneys. There is now evidence of its contribution to physiological processes such as renal postnatal development, renin secretion, the tubuloglomerular feedback, sodium excretion. COX-2, the key regulatory enzyme in the eicosanoids synthesis, it is expressed in the thick ascending limb of Henle (TAL) of the kidney. We have been working the hypothesis that COX-2 is regulated by a negative feedback loop by PGE2, as COX-2 inhibitors (Coxibs) increase the enzyme. We studied COX-2 under inhibition, EP3 receptor antagonist, and synthetic PGE2. COX-2 was quantified by Western blot, morphometric analysis, gene expression by qRT-PCR. Coxibs increase COX-2 mRNA and protein expression, activation of the EP3 receptor downregulated the enzyme. The increased COX-2 evidenced a recruitment phenomenon in which subtypes of TAL cells, which do not express COX-2 under basal conditions, are induced to express the enzyme. Newly expressing cells may be important for long-term physiological regulation via modifying the number of COX-2- positive cells in the TAL.We postulate that COX-2 levels are regulated by a negative feedback loop mediated by PGE2 acting on its rEP3 receptor in the TAL nephron segment. Supported by Grants Fondecyt 1130741, PBF 12-2007 and SQM.