DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.
DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.
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DOI：
10.1371/journal.pone.0138535
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lammert E
中科院分区：
文献类型：
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作者：
Jain D;Weber G;Eberhard D;Mehana AE;Eglinger J;Welters A;Bartosinska B;Jeruschke K;Weiss J;Päth G;Ariga H;Seufert J;Lammert E
1型和2型糖尿病的一个显著特征是产生胰岛素的胰腺β细胞的进行性功能障碍和丧失，而炎性细胞因子可引发β细胞死亡。在这里，我们询问由帕金森病基因PARK7编码的抗氧化蛋白DJ-1是否保护胰岛细胞免受细胞因子和链ptozotocin介导的细胞死亡。用多种低剂量链脲佐菌素（MLDS）治疗野生型和DJ-1基因敲除小鼠（KO），诱导炎症β细胞应激和细胞死亡。随后，进行葡萄糖耐量试验，监测血浆胰岛素以及空腹和随机血糖浓度。测定β细胞线粒体形态和胰岛素颗粒数量。采用钙黄蛋白AM/乙二聚体-1染色和TUNEL染色，观察链脲佐菌素和细胞因子对离体野生型和DJ-1型KO胰岛的体外损伤情况。与野生型小鼠相比，DJ-1 KO小鼠在MLDS治疗后发生糖尿病。与同样处理的野生型小鼠相比，mlds处理的DJ-1 KO小鼠胰岛素浓度显著降低，空腹血糖浓度显著升高。与野生型小鼠相比，MLDS治疗后DJ-1 KO小鼠的β细胞凋亡率高出两倍，体外炎症因子导致DJ-1 KO小鼠胰岛β细胞死亡的数量是野生型小鼠的两倍。总之，本研究确定抗氧化蛋白DJ-1能够保护胰岛细胞免受炎症和细胞毒性环境诱导的细胞死亡。
A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson’s disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.