Lack of serum- and glucocorticoid-inducible kinase 3 leads to podocyte dysfunction
Lack of serum- and glucocorticoid-inducible kinase 3 leads to podocyte dysfunction
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血清和糖皮质激素诱导激酶 3 的缺乏会导致足细胞功能障碍。
DOI：
10.1096/fj.201700393rr
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发表时间：
2018-02-01
期刊：
影响因子：
4.8
通讯作者：
Yao, Li-Jun
中科院分区：
文献类型：
--
作者：
Peng, Li-Qin;Zhao, Hong;Yao, Li-Jun
血清和糖皮质激素诱导激酶 3 (SGK3) 是 PI3K 的下游介质，对于维持足细胞的功能完整性至关重要。然而，人们对 SGK3 在足细胞功能中的作用知之甚少。在此，我们证明 SGK3 有助于维持足细胞的完整性。用嘌呤霉素氨基核苷（PAN）处理条件永生化小鼠足细胞（MPC）。 PAN处理抑制SGK3的活性和podocin的表达。在没有 PAN 的情况下，短发夹 RNA (shRNA) 介导的 SGK3 敲低也会降低 podocin 的表达。与对照小鼠相比，阿霉素 (ADR) 治疗的小鼠出现蛋白尿，肾小球 SGK3 表达降低。与 SGK3 在 ADR 效应中的作用一致，与野生型小鼠相比，SGK3 敲除 (KO) 小鼠的肾脏 podocin 表达显着降低，蛋白尿显着升高。电镜显示 SGK3 KO 小鼠足细胞足突部分消失。此外，还发现 SGK3 靶蛋白糖原合酶激酶 3 (GSK3) 在 PAN 和 SGK3 shRNA 处理的 MPC 以及 SGK3 KO 小鼠中显着激活。总而言之，这些数据强烈表明 SGK3 在调节足细胞功能中发挥着重要作用，可能是通过控制 GSK3 的表达和活性来实现的。
Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a downstream mediator of PI3K, which is essential for maintaining the functional integrity of podocytes. However, little is known about the role of SGK3 in podocyte function. Herein, we demonstrated that SGK3 contributes to the maintenance of podocyte integrity. Conditionally immortalized mouse podocyte cells (MPCs) were treated with puromycin aminonucleoside (PAN). PAN treatment inhibited the activity of SGK3 and the expression of podocin. Short hairpin RNA (shRNA)-mediated knockdown of SGK3 also reduced podocin expression in the absence of PAN. Adriamycin (ADR)-treated mice developed proteinuria and had decreased renal glomerular SGK3 expression in comparison to control mice. Consistent with a role for SGK3 in the ADR effect, SGK3 knockout (KO) mice had markedly reduced kidney podocin expression and significantly elevated proteinuria compared with wild-type mice. Electron microscopy revealed that SGK3 KO mice displayed partial effacement of podocyte foot processes. Further, a SGK3 target protein, glycogen synthase kinase-3 (GSK3), was discovered to be dramatically activated in PAN and SGK3 shRNA-treated MPCs and in SGK3 KO mice. Taken together, these data strongly suggest that SGK3 plays a significant role in regulating podocyte function, likely by controlling the expression and activity of GSK3.