Tumor Necrosis Factor Receptor-Associated Protein 1 Protects against Mitochondrial Injury by Preventing High Glucose-Induced mPTP Opening in Diabetes
Tumor Necrosis Factor Receptor-Associated Protein 1 Protects against Mitochondrial Injury by Preventing High Glucose-Induced mPTP Opening in Diabetes
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DOI：
10.1155/2020/6431517
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发表时间：
2020-03-06
影响因子：
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通讯作者：
Zhao, Tongfeng
中科院分区：
文献类型：
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作者：
Liu, Lerong;Zhang, Lingxiao;Zhao, Tongfeng
糖尿病肾病（DKD）已成为全球终末期肾病的主要原因。肾小管上皮细胞凋亡和肾小管萎缩已被认为是 DKD 严重程度和进展的指标，但其机制仍不清楚。肿瘤坏死因子受体相关蛋白 1 (TRAP1) 在细胞凋亡中发挥关键作用。本研究的目的是调查 TRAP1 在 DKD 中的保护作用并研究潜在的潜在机制。高糖（HG）条件下NRK-52e细胞中TRAP1表达降低，线粒体受损。 TRAP1的过度表达改善了HG诱导的细胞凋亡，增加了细胞活力，维持了线粒体形态、三磷酸腺苷（ATP）水平和线粒体膜电位（MMP），并缓冲了氧化应激，而TRAP1敲低则加剧了这些影响。 TRAP1的保护作用可能是通过抑制线粒体通透性转换孔（mPTP）开放来发挥的，并且通过mPTP开放抑制剂环孢素A（CsA）治疗可以部分逆转TRAP1敲低造成的损伤。在体内，在 STZ 治疗的 DKD 大鼠中，注射 AAV2/9 上调 TRAP1 表达可预防肾功能障碍，改善组织病理学变化，维持线粒体形态和功能，并减少细胞凋亡和活性氧 (ROS)。因此，我们的结果表明，TRAP1 通过防止 mPTP 异常开放和维持线粒体结构和功能来改善糖尿病引起的肾损伤，这可能被视为 DKD 治疗的潜在靶点。
Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Renal tubular epithelial cell apoptosis and tubular atrophy have been recognized as indicators of the severity and progression of DKD, while the mechanism remains elusive. Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays critical roles in apoptosis. The aim of this study was to investigate the protective role TRAP1 plays in DKD and to study the potential underlying mechanisms. TRAP1 expression was decreased, and mitochondria were injured in NRK-52e cells under high-glucose (HG) conditions. The overexpression of TRAP1 ameliorated HG-induced apoptosis, increased cell viability, maintained mitochondrial morphology, adenosine triphosphate (ATP) levels, and mitochondrial membrane potential (MMP), and buffered oxidative stress, whereas TRAP1 knockdown aggravated these effects. The protective effects of TRAP1 may be exerted via the inhibition of mitochondrial permeability transition pore (mPTP) opening, and the damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor cyclosporin A (CsA). In vivo, TRAP1 expression upregulation by AAV2/9 injection prevented renal dysfunction, ameliorated histopathological changes, maintained mitochondrial morphology and function, and reduced apoptosis and reactive oxygen species (ROS) in STZ-treated DKD rats. Thus, our results suggest that TRAP1 ameliorates diabetes-induced renal injury by preventing abnormal mPTP opening and maintaining mitochondrial structure and function, which may be treated as a potential target for DKD treatment.