Figure 7. Working model of dual-receptor drug mechanisms in epithelial and non-epithelial tissues.

Left Panel: Epithelial MR target tissues (e.g., kidney, colon, skin) co-express the HSD11B2 enzyme to prevent over-activation of the MR by glucocorticoids. This protein metabolizes 11β-hydroxysteroids (cortisol and prednisolone) into their inactive ketone states (cortisone and prednisone) within that tissue. Aldosterone is not metabolized by HSD11B2, thus enabling aldosterone-specific signaling in vivo. We find that aldosterone challenge increases kidney size, whereas prednisolone treatment does not, consistent with this model. Right Panel: Non-epithelial MR target tissues express the MR but do not express the HSD11B2 enzyme (heart, brain, skin, fat, immune cells). These tissues may have increased risk of damage from MR activation by glucocorticoids. The heart is particularly important here, as (1) DMD patients naturally develop cardiomyopathy, and (2) a “second hit” provided by the DMD disease could worsen MR-mediated heart pathologies (such a “second hit” is seen in other aldosterone models). We find that both aldosterone and prednisolone increase mdx heart size and fibrosis, consistent with increased MR activation. Both Panels: Vamorolone is a potent MR antagonist that protects both epithelial and non-epithelial tissue types. (Black = physiological ligands, Blue = Vamorolone, Red = Prednisolone; Aldo = Aldosterone, Cort = Cortisol, HSD11B2 = 11β-hydroxysteroid dehydrogenase, Pred = Prednisolone, Vam = Vamorolone).