Regulation of cyclooxygenase-2 (COX-2) in rat renal cortex by adrenal glucocorticoids and mineralocorticoids

Production of prostaglandins involved in renal salt and water homeostasis i s modulated by regulated expression of the inducible form of cyclooxygenase -2 (COX-2) at restricted sites in the rat renal cortex. Because inflammator y COX-2 is suppressed by glucocorticoids, and prostaglandin levels in the k idney are sensitive to steroids, the sensitivity of COX expression to adren alectomy (ADX) was investigated. By 2 weeks after ADX in mature rats, corti cal COX-2 immunoreactivity increased 10-fold in the cortical thick ascendin g limb and macula densa, The constitutive isoform, COX-1, was unchanged. Th e magnitude of the changes and specificity of COX-2 immunoreactivity were v alidated by in situ hybridization histochemistry of COX-2 mRNA and Western blot analysis. Increased COX-2 activity (>5-fold) was documented by using a specific COX-2 inhibitor. The COX-2 up-regulation in ADX rats was reversed by replacement therapy with either corticosterone or deoxycorticosterone a cetate. In normal rats, inhibition of glucocorticoid receptors with RU486 o r mineralocorticoid receptors with spironolactone caused up-regulation of r enal cortical COX-2, These results indicate that COX-2 expression in situ i s tonically inhibited by adrenal steroids, and COX-2 is regulated by minera locorticoids as well as glucocorticoids.