steroids 74 ( 2 0 0 9 ) 1–6 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/steroids Review Interactions of mineralocorticoids and glucocorticoids in epithelial target tissues revisited David J. Morris a,∗ , Syed A. Latif a , Andrew S. Brem b a The Department of Laboratory Medicine, The Miriam Hospital, Brown University Medical School, Providence, RI, United States b The Department of Pediatrics (Nephrology), Rhode Island Hospital, Brown University Medical School, Providence, RI, United States article info Article history: Received 7 August 2008 Received in revised form 6 October 2008 Accepted 7 October 2008 Published on line 21 October 2008 Keywords: Glucocorticoids Mineralocorticoids 11-HSD2 Kidney Sodium transport abstract The interplay between mineralocorticoids (MCs) and glucocorticoids (GCs) in sodium trans- porting epithelia is complex and only partially understood. In seminal papers published in the years soon after the discovery of aldosterone, various investigators experimentally observed that mineralocorticoid-induced renal sodium retention could only be reliably measured in adrenalectomized animals. Addition of endogenous GCs or their 11-dehydro metabolites blunted the antinatriuretic action of aldosterone and 11-dehydro-GCs decreased binding of aldosterone to mineralocorticoid receptors (MR). Under normal circumstances, endogenous GCs alone do not induce sodium transport in MC responsive epithelia yet these same GCs are able to activate MR and induce sodium transport if the enzyme 11-HSD2 is inhibited. Given the physiologic concentrations of both MCs and GCs, it is likely that the local epithelial cell exposure to GCs is great enough to allow GC binding to MR despite the pres- ence of 11-HSD2. Thus other factors supplement the receptor selectivity role suggested for 11-HSD2. Why GCs bind to MR under one set of conditions and produce no effect and under different sets of conditions (11-HSD2 inhibition) elicit sodium transport remains a puzzle to be solved. What is clear is that a dual role for 11-HSD2 is emerging; first as the putative “guardian” over the MR reducing GC binding, and second as a source for 11-dehydro-GCs, which may serve as endogenously and locally produced “spironolactone–like substances”, which may thus attenuate aldosterone-induced sodium transport. © 2008 Elsevier Inc. All rights reserved. Glucocorticoids normally do not induce active sodium trans- port in mineralocorticoid responsive epithelial tissues, but can stimulate significant kaliuresis in the mammalian kidney. The mineralocorticoid sensitive segments of the mammalian kidney [1–3] and models of the cortical collecting duct, like the toad urinary bladder [4,5], contain the enzyme 11- hydroxysteroid dehydrogenase type 2 (11-HSD2), an enzyme which was thought to metabolize endogenous glucocorticoids * Corresponding author at: Department of Laboratory Medicine, The Miriam Hospital, 164 Summit Avenue, Providence RI 02906, United States. Tel.: +1 401 793 4231. E-mail address: Dmorris@Lifespan.org (D.J. Morris). before they have an opportunity to bind to the mineralo- corticoid receptor (MR) and induce a biological effect [1,3,6]. Inhibitors like the licorice derivatives glycyrrhetinic acid and carbenoxolone can overcome this “guardian” action of 11- HSD2 allowing GCs to activate MR [7]. These time-honored concepts however, do not fully explain a number of salient observations reported in the literature, many from bioassays conducted 25–50 years ago; because of their age they have 0039-128X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2008.10.005