Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities

Abstract

Background/Aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. Methods: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. Results: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. Conclusion: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury.

Dietary Phytoecdysteroids

“…Recently (Lu et al 2018a, b), it has been suggested that ecdysone (E, which is rarely a major phytoecdysteroid) has detrimental effects on renal function in mice at a dose of 6 μg/g/d, bringing about glomerular injury and proteinuria. The authors propose that E acts as a mimic of aldosterone, activating the mineralocorticoid nuclear receptor (MR), and that the detrimental effects can largely be blocked by spironolactone, an antagonist of MR. As yet, it is not known if these effects are common to other ecdysteroids, e.g., 20E.…”

Aldosterone is a possible new stimulating factor for promoting vascular calcification

“…Additionally, aldosterone plays a key role in the pathophysiology of hypertension, chronic heart failure [9], myocar-dial infarction remodeling [6][7][8]. The mineralocorticoid receptor (MR) activated by aldosterone can increase the synthesis of collagen [10], induce inflammation [11,12], modulate oxidative stress [13][14][15], promote cell migration [16], and induce apoptosis [17,18]. Aldosterone can also increase calcification in vascular smooth muscle cells [19,20].…”