Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling.
Activation of mineralocorticoid receptor by ecdysone, an adaptogenic and anabolic ecdysteroid, promotes glomerular injury and proteinuria involving overactive GSK3β pathway signaling.
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蜕皮激素（一种适应原和合成代谢蜕皮激素）激活盐皮质激素受体，促进肾小球损伤和蛋白尿，涉及过度活跃的 GSK3β 通路信号传导
DOI：
10.1038/s41598-018-29483-7
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发表时间：
2018-08-15
影响因子：
4.6
通讯作者：
Gong R
中科院分区：
文献类型：
--
作者：
Lu M;Wang P;Ge Y;Dworkin L;Brem A;Liu Z;Gong R
蜕皮激素是一种节肢动物蜕皮激素，并已作为非雄激素天然合成代谢和适应原上市。然而，蜕皮激素的安全性在很大程度上是不确定的。蜕皮激素治疗2周后，小鼠出现蛋白尿，伴有肾小球损伤的组织学体征，包括肥大、系膜扩张、轻度肾小球硬化和足细胞损伤。蜕皮激素的直接肾小球病变活性似乎有贡献，因为除了蜕皮激素培养的肾小球细胞诱导细胞病变的变化，包括细胞凋亡，系膜细胞的活化，足细胞形状的变化和足细胞标志物的表达减少。为了探索致病作用的分子靶点，我们采用了化合物-蛋白质相互作用的计算机模拟系统，并确定盐皮质激素受体（MR）是与蜕皮激素相互作用的顶级蛋白质之一。蜕皮激素的分子结构与醛固酮等盐皮质激素高度同源。此外，蜕皮激素能够诱导和激活MR，这一点在体外和体内的肾小球细胞中均有MR核积聚。从机制上讲，糖原合成酶激酶（GSK）3β，最近已被牵连在肾小球损伤和蛋白尿的发病机制，是过度激活的肾小球在蜕皮激素治疗的小鼠，伴随着各种肾小球病变的变化。相反，选择性阻断MR的螺内酯在很大程度上消除了蜕皮激素的体外细胞病变效应，减轻了蜕皮激素处理小鼠的蛋白尿和肾小球病变，并减轻了肾小球中GSK 3 β的过度活性。总之，蜕皮激素似乎能够激活MR，从而促进肾小球损伤和蛋白尿，涉及过度活跃的GSK 3 β途径信号传导。
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 anin silicomodeling 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 bothin vitroandin vivofollowing ecdysone treatment. Mechanistically, glycogen synthase kinase (GSK) 3β, 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 ecdysonein vitroand attenuated albuminuria and glomerular lesions in ecdysone treated mice, associated with a mitigated GSK3β overactivity in glomeruli. Altogether, ecdysone seems able to activate MR and thereby promote glomerular injury and proteinuria involving overactive GSK3β pathway signaling.
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影响因子：
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作者：
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