Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling

Ecdysone is an arthropod molting hormone and has been marketed as a non-androgenic natural anabolic and adaptogen. However, the safety profile of ecdysone is largely undetermined. After ecdysone treatment for 2 weeks, mice developed albuminuria with histologic signs of glomerular injury, including hypertrophy, mesangial expansion, mild glomerulosclerosis and podocyte injury. A direct glomerulopathic activity of ecdysone seems to contribute, since addition of ecdysone to cultured glomerular cells induced cytopathic changes, including apoptosis, activation of mesangial cells, podocyte shape changes and a decreased expression of podocyte markers. To explore the molecular target responsible for the pathogenic actions, we employed an in silico modeling system of compound-protein interaction and identified mineralocorticoid receptor (MR) as one of the top-ranking proteins with putative interactions with ecdysone. The molecular structure of ecdysone was highly homologous to mineralocorticoids, like aldosterone. Moreover, ecdysone was capable of both inducing and activating MR, as evidenced by MR nuclear accumulation in glomerular cells both in vitro and in vivo following ecdysone treatment. Mechanistically, glycogen synthase kinase (GSK) 3 beta, which has been recently implicated in pathogenesis of glomerular injury and proteinuria, was hyperactivated in glomeruli in ecdysone-treated mice, concomitant with diverse glomerulopathic changes. In contrast, spironolactone, a selective blockade of MR, largely abolished the cytopathic effect of ecdysone in vitro and attenuated albuminuria and glomerular lesions in ecdysone treated mice, associated with a mitigated GSK3 beta overactivity in glomeruli. Altogether, ecdysone seems able to activate MR and thereby promote glomerular injury and proteinuria involving overactive GSK3 beta pathway signaling.