title: Interactions between 11beta-hydroxysteroid dehydrogenase and COX-2 in kidney.
abstract: The syndrome of apparent mineralocorticoid excess (SAME) is an autosomal recessive form of salt-sensitive hypertension caused by deficiency of the kidney type 2 11beta-hydroxysteroid dehydrogenase (11betaHSD2). In this disorder, cortisol is not inactivated by 11betaHSD2, occupies mineralocorticoid receptors (MRs), and causes excessive sodium retention and hypertension. In renal medulla, prostaglandins derived from cyclooxygenase-2 (COX-2) stimulate sodium and water excretion, and renal medullary COX-2 expression increases after mineralocorticoid administration. We investigated whether medullary COX-2 also increases in rats with 11betaHSD2 inhibition and examined its possible role in the development of hypertension. 11betaHSD2 inhibition increased medullary and decreased cortical COX-2 expression in adult rats and induced high blood pressure in high-salt-treated rats. COX-2 inhibition had no effect on blood pressure in control animals but further increased blood pressure in high-salt-treated rats with 11betaHSD2 inhibition. COX-1 inhibition had no effect on blood pressure in either control or experimental animals. 11betaHSD2 inhibition also led to medullary COX-2 increase and cortical COX-2 decrease in weaning rats, primarily through activation of MRs. In the suckling rats, medullary COX-2 expression was very low, consistent with a urinary concentrating defect. 11betaHSD2 inhibition had no effect on either cortical or medullary COX-2 expression in the suckling rats, consistent with low levels of circulating corticosterone in these animals. These data indicate that COX-2 plays a modulating role in the development of hypertension due to 11betaHSD2 deficiency and that 11betaHSD2 regulates renal COX-2 expression by preventing glucocorticoid access to MRs during postnatal development.
authors.affiliation: George O'Brien Center for Kidney and Urologic Diseases and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-4794, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007672:Kidney Cortex / Q000201:enzymology; D007679:Kidney Medulla / Q000201:enzymology; D015735:Mifepristone / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D015735:Mifepristone; D019695:Glycyrrhizic Acid; D015067:17-Hydroxysteroid Dehydrogenases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases