Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway
Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway
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DOI：
10.3390/cells7120226
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发表时间：
2018-12-01
期刊：
影响因子：
6
通讯作者：
Sabry, Dina
中科院分区：
文献类型：
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作者：
Ebrahim, Nesrine;Ahmed, Inas A.;Sabry, Dina
背景：糖尿病肾病（diabetic nephropathy，DN）是糖尿病的严重并发症，也是终末期肾病的常见原因。自噬对高血糖引起的肾脏损伤具有防御作用。间充质干细胞（MSC）来源的exosomes目前被认为是治疗慢性肾损伤的一种新的有前途的治疗方法。然而，外泌体对DN的肾脏保护机制尚不完全清楚。我们研究了MSC衍生的外泌体在增强自噬活性方面的潜在作用及其对DN的影响。在我们的研究中，我们使用了五组大鼠：对照; DN;用外来体治疗的DN;用3-甲基腺嘌呤（3-MA）和氯喹（自噬抑制剂）治疗的DN;以及用3-甲基腺嘌呤（3-MA），氯喹和外来体治疗的DN组。我们评估了肾功能、形态学和纤维化。此外，检测自噬标志物雷帕霉素的机制靶点（mTOR）、Beclin-1、轻链-3（LC 3-II）和LC 3-II/LC 3-I的比率。此外，电子显微镜用于检测自噬体。结果如下：外泌体显著改善肾功能，并显示肾组织的组织学恢复，其中LC 3和Beclin-1显著增加，mTOR和肾组织纤维化标志物表达显著降低。自噬抑制剂氯喹和3-MA可部分消除上述效应。结论：在链脲佐菌素诱导的糖尿病大鼠模型中，外泌体诱导的自噬可以减轻DN。
Background: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. Mesenchymal stem cell (MSC)-derived exosomes are currently considered as a new promising therapy for chronic renal injury. However, the renal-protective mechanism of exosomes on DN is not completely understood. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their effect on DN. In our study, we used five groups of rats: control; DN; DN treated with exosomes; DN treated with 3-methyladenine (3-MA) and chloroquine (inhibitors of autophagy); and DN treated with 3-methyladenine (3-MA), chloroquine, and exosome groups. We assessed renal function, morphology, and fibrosis. Moreover, ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved renal function and showed histological restoration of renal tissues, with significant increase of LC3 and Beclin-1, and significant decrease of mTOR and fibrotic marker expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitors chloroquine and 3-MA. Conclusion: We conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus.