Interactions between 11β-hydroxysteroid dehydrogenase and COX-2 in kidney.

The syndrome of apparent mineralocorticoid excess (SAME) is an autosomal recessive form of salt-sensitive hypertension caused by deficiency of the kidney type 2 11β-hydroxy steroid dehydrogenase (11βHSD2). In this disorder, cortisol is not inactivated by 11βHSD2, 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 11βHSD2 inhibition and examined its possible role in the development of hypertension. 11βHSD2 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 11βHSD2 inhibition. COX-1 inhibition had no effect on blood pressure in either control or experimental animals. 11βHSD2 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. 11βHSD2 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 11βHSD2 deficiency and that 11βHSD2 regulates renal COX-2 expression by preventing glucocorticoid access to MRs during postnatal development. [ABSTRACT FROM AUTHOR]