Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin.
Serum and Glucocorticoid-Inducible Kinase 3/Nedd4-2 Signaling Pathway Participates in Podocyte Injury by Regulating the Stability of Nephrin.
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DOI：
10.3389/fphys.2021.810473
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发表时间：
2021
影响因子：
4
通讯作者：
Yao LJ
中科院分区：
文献类型：
--
作者：
Dong QQ;Li ZF;Zhang H;Shu HP;Tu YC;Liao QQ;Yao LJ
血清和糖皮质激素诱导激酶3（SGK 3）通过调节podocin和CD 2相关蛋白的蛋白水平参与维持足细胞功能。Nephrin也是足细胞的裂膜蛋白之一，但SGK 3是否通过调节nephrin水平参与足细胞损伤仍不清楚。在这项研究中，我们专注于SGK 3是否影响nephrin水平及其相关机制。在阿霉素（ADR）诱导的足细胞损伤小鼠模型中，SGK 3和nephrin蛋白水平显著降低。SGK 3表达与尿蛋白量呈负相关，与nephrin水平呈正相关。在ADR处理的条件永生化小鼠足细胞（MPC）中，nephrin和SGK 3的蛋白水平被抑制，而SGK 3的组成性表达逆转了ADR诱导的nephrin蛋白水平的下降。此外，ADR处理或SGK 3失活增强了MPC中nephrin的泛素-蛋白酶体降解，并显著激活了SGK 3的下游效应蛋白，神经前体细胞表达发育下调的蛋白4亚型2（Nedd 4 -2）和糖原合成酶激酶-3 β（GSK 3 β）。类似地，Nedd 4 -2或GSK 3 β过表达导致Nedd 4 -2或GSK 3 β活性增加，并显著下调nephrin水平。有趣的是，泛素介导的nephrin蛋白降解受Nedd 4 -2而不是GSK 3 β调节。总之，在ADR诱导的足细胞损伤模型中，SGK 3失活通过增加Nedd 4 -2和GSK 3 β活性下调nephrin水平;特别是，发现SGK 3/Nedd 4 -2信号通路参与泛素介导的nephrin蛋白酶体降解。
Serum and glucocorticoid-inducible kinase 3 (SGK3) is involved in maintaining podocyte function by regulating the protein levels of podocin and CD2-associated protein. Nephrin is also one of the slit diaphragm proteins of podocytes, but whether SGK3 participates in podocyte injury by regulating the levels of nephrin remains unclear. In this study, we focused on whether SGK3 affects nephrin levels and the mechanisms involved in the same. In the kidneys of adriamycin (ADR)-induced podocyte injury mouse model, the protein levels of SGK3 and nephrin were significantly decreased. Furthermore, the expression of SGK3 was negatively correlated with the output of proteinuria, and positively correlated with the levels of nephrin. In ADR-treated conditionally immortalized mouse podocyte cells (MPCs), the protein levels of nephrin and SGK3 were inhibited, while the constitutive expression of SGK3 reversed the ADR-induced decline in nephrin protein levels. Furthermore, ADR treatment or SGK3 inactivation enhanced the ubiquitin-proteasome degradation of nephrin in MPCs, and dramatically activated downstream effector proteins of SGK3, neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2) and glycogen synthase kinase-3 β (GSK3β). Similarly, Nedd4-2 or GSK3β overexpression resulted in increased activity of Nedd4-2 or GSK3β, and significantly downregulated nephrin levels. Interestingly, ubiquitin-mediated protein degradation of nephrin was regulated by Nedd4-2, rather than by GSK3β. In summary, SGK3 inactivation downregulated the levels of nephrin by increasing Nedd4-2 and GSK3β activity in ADR-induced podocyte injury model; in particular, the SGK3/Nedd4-2 signaling pathway was found to be involved in ubiquitin-mediated proteasome degradation of nephrin.
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影响因子：
5
作者：
Matsui, Isao;Ito, Takahito;Hori, Masatsugu
通讯作者：
Hori, Masatsugu
影响因子：
4.8
作者：
Quack, Ivo;Woznowski, Magdalena;Sellin, Lorenz
通讯作者：
Sellin, Lorenz
DOI：
10.1073/pnas.0504166102
发表时间：
2005-07-12
影响因子：
11.1
作者：
Lehtonen, S;Ryan, JJ;Farquhar, MG
通讯作者：
Farquhar, MG
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影响因子：
3.4
作者：
Guo J;Yang L;Qiao Y;Liu Z
通讯作者：
Liu Z
影响因子：
120.1
作者：
Cohen, P;Goedert, M
通讯作者：
Goedert, M