Interference of corticosteroids with prostaglandin E2 synthesis at the level of cyclooxygenase-2 mRNA expression in kidney cells.
In the kidney, prostanoids play a role as vasoactive and immunomodulatory mediators. One of the main biosynthetic enzymes, the inducible cyclooxygenase-2 (EC 1.14.99.1, Cox-2), has been recognized as a target of glucocorticoids. Therefore, we investigated whether the physiologically active corticosteroid aldosterone in the kidney might also interfere with prostaglandin (PG) synthesis. In two cell types, an epithelial cell line of tubular origin (MDCK) and rat renal mesangial cells, PGE2, release, Cox activity and Cox mRNA expression were determined after stimulation with phorbol ester and IL-1 beta, respectively. An increase in PGE2 release and Cox activity was observed, which correlated with an increase in Cox-2 mRNA expression. In MDCK cells, both dexamethasone and aldosterone were equally effective, suppressing all parameters measured by approximately 60%. A similar effect of aldosterone was also seen in mesangial cells, whereas dexamethasone was far more potent (> 90% inhibition at 10(-6) M). Whole cell binding assays showed the same number of receptors for aldosterone in both cell types (approximately 70,000 receptors/cell) but more than ten times higher receptor numbers for dexamethasone in mesangial cells than in MDCK cells (90,000 vs. 6000 receptors/cell). Receptor affinities of the corticosteroids were comparable. Thus, interaction of the corticosteroids with their cognate receptors was not sufficient to explain their different potencies but indicated the involvement of more complex regulatory mechanisms. Pathophysiologically, inhibition of PGE2 synthesis by aldosterone may play a role in the induction of hypertension by high concentrations of aldosterone.
Schaefers
H J
HJ
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Germany.
Goppelt-Struebe
M
M
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004285:Dogs; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D007527:Isoenzymes; D012333:RNA, Messenger; D011987:Receptors, Steroid; D000450:Aldosterone; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone