AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4.
AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4.
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腹膜透析中 AKT 对间皮间质转化的调节受 smurf2 和去泛素化酶 USP4 的调节
DOI：
10.1186/s12860-015-0055-7
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发表时间：
2015-03-06
期刊：
影响因子：
--
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Xiao L;Peng X;Liu F;Tang C;Hu C;Xu X;Wang M;Luo Y;Yang S;Song P;Xiao P;Kanwar YS;Sun L
转化生长因子-β-1(转化生长因子-β-1)在腹膜透析(PD)的间皮-间充质转化过程中起关键作用。然而，Akt在帕金森病MMT转化中的作用尚不清楚。在这项研究中，我们观察到蛋白激酶B(Akt)的磷酸化形式，称为PACT，在PD小鼠的腹膜中上调。在PD治疗的小鼠和转化生长因子-β-1诱导的人腹膜间皮细胞(HPMC)中，PAKT的上调与Smad泛素化调节因子2(S-MURF2)、波形蛋白和纤维连接蛋白(FN)的表达增加平行，与母亲抗十碳瘫痪同系物7(SMAD7)和小带闭锁蛋白1(ZO-1)的表达减少相平行。用PI3K/Akt抑制剂LY294002在体内或在体外用Akt显性阴性(Akt-dN)质粒处理细胞后，上述变化均被逆转。转化生长因子受体I(T-βR-I)、Smad7、ZO-1、Vimentin和FN在转化生长因子受体I(T-βR-I)中的表达在转化生长因子受体1诱导下表达增加。此外，抑制泛素羧基末端水解酶4可降低转化生长因子β1诱导的TβR-I的表达，并逆转Smad7、SMurf2、ZO-1和Vimentin的表达变化。此外，转化生长因子-β-1增强了S-β-2和Smad7之间的相互作用，而减少了T-SmadR-I和S-mRf2之间的联系。这些相互作用分别被Akt-dN和USP4 siRNA处理逆转。这些数据表明，Akt通过SMurf2和/或Smad7降解介导了PD中的MMT，同时可能通过Usp4维持TβRI的稳定性。
Transforming growth factor-β1 (TGF-β1) plays a key role in mesothelial-to-mesenchymal transition (MMT) during peritoneal dialysis (PD). However, the role of Akt in MMT transformation in PD is not clear. In this study, we observed that the phosphorylated form of protein kinase B (Akt), termed as pAkt, was up-regulated in the peritoneum of mice undergoing PD. It was associated with thickening of the peritoneum and up-regulation of TGF-β1. Upregulation of pAkt paralleled with the increased expression of Smad ubiquitination regulatory factor 2 (Smurf2), Vimentin and fibronectin (FN), and decreased expression of mothers against decapentaplegic homolog 7 (Smad7) and Zonula Occludens protein 1(ZO-1) in mice undergoing PD treatment and in TGF-β1 induced human peritoneal mesothelial cells (HPMCs). These changes were reversed with the treatment of a PI3K/Akt inhibitor LY294002 in vivo or in cells transfected with Akt dominant-negative (Akt-DN) plasmids in vitro. Increased Smurf2 expression in HPMCs, induced by TGF-β1 was accompanied with altered expression of Transforming growth factor receptor I (TβR-I), Smad7, ZO-1, Vimentin and FN via Akt modulation. In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- β1-induced expression of TβR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin. Moreover, TGF-β1 accentuated the interactions between Smurf2 and Smad7, while reduced the association between TβR-I and Smurf2. These interactions were reversed by the treatment of Akt-DN and USP4 siRNA, respectively. These data implied that Akt mediated MMT in PD via Smurf2 modulation/and or Smad7 degradation while conceivably maintaining the TβRI stability, most likely by the USP4.
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