MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling.
MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling.
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MDM2 通过 Notch1 信号传导参与高葡萄糖诱导的足细胞有丝分裂灾难
DOI：
10.1111/jcmm.13253
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Tang H;Lei CT;Ye C;Gao P;Wan C;Chen S;He FF;Wang YM;Su H;Zhang C
足细胞损伤和耗竭是糖尿病肾病（DN）发病机制中的重要环节。作为终末分化的细胞，足细胞被限制在“有丝分裂后”状态并且不能再生。重新进入有丝分裂期将导致足细胞灾难性死亡，定义为有丝分裂灾难（MC）。小鼠双微体2（MDM 2）是一种细胞周期调控因子，广泛表达于包括足细胞在内的肾脏驻留细胞中。在这里，我们探讨是否MDM 2参与足细胞MC在高血脂症。我们在DN患者中发现异常有丝分裂足细胞多核化。在体外，经高糖（HG）处理的培养足细胞也显示有丝分裂标志物上调和有丝分裂状态异常，并伴有MDM 2表达升高。HG暴露迫使足细胞进入S期并绕过G2/M检查点，Ki 67、cyclin B1、Aurora B和p-H3的表达增强。MDM 2基因缺失部分逆转HG诱导的足细胞有丝分裂期重新进入。此外，HG诱导的足细胞损伤可通过MDM 2敲低而减轻，但不能通过Nutlin-3a（MDM 2-p53相互作用的抑制剂）减轻。有趣的是，敲低MDM 2或MDM 2过表达分别显示Notch 1信号传导的抑制或激活。此外，Notch 1的基因沉默阻止HG介导的足细胞MC。总之，高糖上调MDM 2表达并导致足细胞MC。Notch 1信号传导是MDM 2介导足细胞中HG诱导的MC的重要下游途径。
Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in ‘post‐mitosis’ state and unable to regenerate. Re‐entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi‐nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up‐regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p‐H3. Genetic deletion of MDM2 partly reversed HG‐induced mitotic phase re‐entering of podocytes. Moreover, HG‐induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin‐3a, an inhibitor of MDM2‐p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG‐mediated podocyte MC. In conclusion, high glucose up‐regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG‐induced MC in podocytes.
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影响因子：
3.2
作者：
Maezawa Y;Takemoto M;Yokote K
通讯作者：
Yokote K
影响因子：
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作者：
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通讯作者：
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影响因子：
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