MDM2 Contributes to High Glucose-Induced Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation via Notch1.
MDM2 Contributes to High Glucose-Induced Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation via Notch1.
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DOI：
10.1038/s41598-017-10927-5
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发表时间：
2017-09-04
影响因子：
4.6
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Lei CT;Tang H;Ye C;You CQ;Zhang J;Zhang CY;Xiong W;Su H;Zhang C
小鼠双微体2（MDM 2）是一种E3-泛素连接酶，对多种生物学功能至关重要。先前的数据已经揭示了MDM 2在肾脏稳态中不可或缺的作用。然而，其在高血糖条件下肾小球系膜细胞（GMC）增殖和细胞外基质（ECM）积聚中的作用尚不清楚。在本研究中，我们发现高糖处理的GMCs中MDM 2蛋白水平显著上调，而通过siRNA敲低MDM 2可以减弱高糖诱导的ECM积累和GMCs增殖。出乎意料的是，Nutlin-3a，一种MDM 2-p53相互作用阻断剂，在体内保护糖尿病小鼠免受肾损伤和在体外减轻高葡萄糖诱导的ECM积累方面没有益处。有趣的是，我们发现Notch 1信号通路的激活在高糖暴露的GMCs中被MDM 2耗竭明显减弱。然而，Numb，MDM 2的底物，抑制Notch 1信号，被发现不参与MDM 2和Notch 1协会。此外，我们的研究结果表明，MDM 2与Notch 1胞内结构域（NICD 1）相互作用，不依赖于Numb，并调节NICD 1的泛素化状态。总的来说，我们的数据表明，MDM 2在高糖诱导的GMC增殖和ECM积累中起关键作用，通过调节Notch 1信号通路的激活，以泛素化依赖的方式。
Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation. Unexpectedly, Nutlin-3a, a MDM2-p53 interaction blocker, had no benefit in protecting diabetic mice from renal impairment in vivo and in alleviating high glucose-induced ECM accumulation in vitro. Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure. However, Numb, a substrate of MDM2 which suppresses Notch1 signaling, was found not to be involved in the MDM2 and Notch1 association. Moreover, our findings demonstrated that MDM2 interacted with Notch1 intracellular domain (NICD1) independent of Numb and regulated the ubiquitination status of NICD1. Collectively, our data propose a pivotal role of MDM2 in high glucose-induced GMC proliferation and ECM accumulation, via modulating the activation of Notch1 signaling pathway in an ubiquitination-dependent way.
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影响因子：
8.2
作者：
Hadjadj, Samy;Cariou, Bertrand;Marre, Michel
通讯作者：
Marre, Michel
影响因子：
19.6
作者：
Mulay, Shrikant R.;Thomasova, Dana;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
DOI：
10.1093/jnci/86.17.1297
发表时间：
1994-09-07
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
FLORENES, VA;MAELANDSMO, GM;FODSTAD, O
通讯作者：
FODSTAD, O
影响因子：
7.7
作者：
Lin CL;Wang FS;Hsu YC;Chen CN;Tseng MJ;Saleem MA;Chang PJ;Wang JY
通讯作者：
Wang JY
影响因子：
5.4
作者：
Liu, Yan;Xing, Zhao-Bin;Zhang, Jing-Hua
通讯作者：
Zhang, Jing-Hua