11β-Hydroxysteroid Dehydrogenase-2 and Salt-Sensitive Hypertension

Glucocorticoid intracellular metabolism, catalyzed by the 2 isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD), determines the corticosteroid action on target tissues.1 11β-HSD1 functions as a reductase in most cells and catalyzes the regeneration of active glucocorticoids, thereby amplifying their action. This isozyme is widely expressed in liver, adipose tissue, muscle, pancreatic islets, and adult brain. 11β-HSD2 is a high-affinity dehydrogenase and inactivates cortisol and corticosterone to the inert product, cortisone. Cortisone in turn can be reactivated through reduction by 11β-HSD1 (Figure 1). The 11β-HSD2 isozyme is highly expressed in the distal nephron and, as we learn here, in the nucleus tractus solitarius. 11β-HSD2 serves to protect the mineralocorticoid receptor (MR) from occupation by cortisol or corticosterone (Figure 2).Figure 1. 11β-HSD1 is predominantly a reductase that catalyzes the NADPH-dependent reduction of cortisone to the active glucocorticoid, cortisol. 11β-HSD2 functions mainly as an NADP-dependent dehydrogenase, inactivating cortisol to cortisone. 11β-HSD indicates 11β-hydroxysteroid dehydrogenase. Adapted from Chapman et al1 with permission of the publisher. Copyright © 2013, the American Physiological Society. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.Figure 2. 11β-HSD2 catalyzes the rapid inactivation of cortisol (compound F) to cortisone (compound E) in the kidney and the nucleus tractus solitarius. Cortisol is intended for the glucocorticoid receptor (GR). However, 11β-HSD2 is absent in the hippocampus, which expresses the mineralocorticoid receptor (MR). At this site, the MR can be activated by cortisol. Because the GR has a 10-fold lower affinity for cortisol than the MR, 11β-HSD1 provides a dynamic range for amplification to impact signaling events. Aldo indicates aldosterone; …