Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization
Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization
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DOI：
10.1111/j.1523-1755.2005.00723.x
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发表时间：
2005-12-01
影响因子：
19.6
通讯作者：
Smoyer, WE
中科院分区：
文献类型：
--
作者：
Ransom, RF;Lam, NG;Smoyer, WE
背景。肾病综合征是儿童和成人常见的肾脏疾病，其特征是肾小球足细胞富含肌动蛋白的足突发生显着的结构变化。尽管糖皮质激素是肾病综合征的主要治疗方法，但糖皮质激素在肾病综合征中的靶细胞和作用机制尚不清楚。在过去的 30 年里，人们推测糖皮质激素通过减少循环淋巴细胞释放可溶性疾病介质来发挥作用。相反，我们假设糖皮质激素通过直接作用于足细胞来发挥其对肾病综合征的有益作用。方法。在存在和不存在米非司酮（以抑制糖皮质激素诱导的转录激活）的情况下用糖皮质激素处理培养的小鼠足细胞，并使用我们之前报道的嘌呤霉素氨基核苷（PAN）诱导的足细胞损伤的体外模型以及通过用latrunculin和细胞松弛素直接破坏肌动蛋白丝来进行攻击。测量细胞活力、肌动蛋白丝分布、总聚合肌动蛋白含量和肌动蛋白调节鸟嘌呤三磷酸酶 (GTPase) 活性。结果。我们证明，用糖皮质激素地塞米松治疗培养的小鼠足细胞既可以保护并增强 PAN 引起的损伤的恢复。地塞米松还可以增加细胞聚合肌动蛋白总量，稳定肌动蛋白丝，使其免受 PAN、latrunculin 或细胞松弛素的破坏，并诱导肌动蛋白调节 GTP 酶 RhoA 的活性显着增加。结论。这些数据表明，与当前的治疗模式相反，糖皮质激素对肾病综合征的有益作用可能至少部分来自对足细胞的直接作用，导致肌动蛋白丝稳定性增强。
Background. Nephrotic syndrome is a common kidney disease in both children and adults that is characterized by dramatic structural changes in the actin-rich foot processes of glomerular podocytes. Although glucocorticoids are the primary treatment for nephrotic syndrome, neither the target cell nor mechanism of action of glucocorticoids in nephrotic syndrome is known. For the last 30 years glucocorticoids have been presumed to act by reducing the release of soluble mediators of disease by circulating lymphocytes. In contrast, we hypothesized that glucocorticoids exert their beneficial effects in nephrotic syndrome by direct action on podocytes.Methods. Cultured murine podocytes were treated with glucocorticoids in the presence and absence of mifepristone (to inhibit glucocorticoid-induced transcriptional activation) and challenged using our previously reported in vitro model of puromycin aminonucleoside (PAN)-induced podocyte injury, as well as by direct disruption of actin filaments with latrunculin and cytochalasin. Cell viability, actin filament distribution, total polymerized actin content, and actin-regulating guanine triphosphatase (GTPase) activities were measured.Results. We demonstrated that treatment of cultured murine podocytes with the glucocorticoid dexamethasone both protected and enhanced recovery from PAN-induced injury. Dexamethasone also increased total cellular polymerized actin, stabilized actin filaments against disruption by PAN, latrunculin, or cytochalasin, and induced a significant increase in the activity of the actin-regulating GTPase RhoA.Conclusion. These data suggest that, contrary to the current therapeutic paradigm, the beneficial effects of glucocorticoids in nephrotic syndrome may result, at least in part, from direct effects on podocytes leading to enhanced actin filament stability.