Diabetic nephropathy (DN) is an increasing threat to human health and regarded to be the leading cause of end-stage renal disease worldwide. Exosomes delivery may play a key role in cross-talk among kidney cells and the progression of DN. However, the mechanisms underlying exosomes in DN remain unclear. The cross-disciplinary study, including in vivo, in vitro, and human studies was conducted to explore the cross-talk between proximal tubular epithelial cells (PTECs) and mesangial cells (MCs) in DN. We purified exosome from PTECs treated with high glucose and db/db mice and assessed their influences in the pathologic change of MCs and downstream signal pathway. Healthy individuals and type 2 diabetic patients were enrolled to examine the role of exosomes in clinical applications. High glucose stimulated PTECs to secrete exosomal miR-92a-1-5p, which was taken-up by glomerular MCs, inducing myofibroblast transdifferentiation (MFT) in vitro and in vivo. PTEC-released exosomal 92a-1-5p decreased reticulocalbin-3 expression, leading to endoplasmic reticulum (ER) stress by downregulating genes essential for ER homeostasis including calreticulin and mesencephalic astrocyte-derived neurotrophic factor. Treatment with miR-92a-1-5p inhibitor ameliorated kidney damage in db/db mice with DN. Urinary miR-92a-1-5p could predict kidney injury in type 2 diabetic patients. PTEC-derived exosomal miR-92a-1-5p modulated the kidney microenvironment in vivo and in vitro models, which altered ER stress and MFT in MCs resulting in DN progression. Further blocking miR-92a-1-5p epigenetic regulatory network could be a potential therapeutic strategy to prevent the progression of DN. Diabetic nephropathy (DN) has been the leading cause of end-stage renal disease worldwide. Exosomes play a principle role in cross-talk of kidney cells and further affect the onset or progression of DN. This study firstly demonstrated the communication between proximal tubular epithelial cells (PTECs) and mesangial cells (MCs) through exosome transmission. PTEC-released exosomal 92a-1-5p induced endoplasmic reticulum stress and epithelial-mesenchymal transition in MCs through reticulocalbin-3 modulation. Kidney damage was rescued in DN mice after treatment with miR-92a-1-5p inhibitor. Moreover, urinary exosomal miR-92a-1-5p could predict DN progression in type 2 diabetic patients. These findings prove the impact of exosomal miR-92a-1-5p on pathophysiologic mechanisms and its potential use in clinical care and prediction of DN.

中文翻译：

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近端小管来源的外泌体通过 miR-92a-1-5p 转移促进糖尿病肾病系膜细胞损伤

糖尿病肾病 (DN) 对人类健康的威胁越来越大，被认为是全球终末期肾病的主要原因。外泌体递送可能在肾细胞间的相互作用和 DN 的进展中发挥关键作用。然而，DN 中外泌体的潜在机制仍不清楚。进行了包括体内、体外和人体研究在内的跨学科研究，以探索 DN 中近端肾小管上皮细胞 (PTEC) 和系膜细胞 (MC) 之间的相互作用。我们从用高糖和 db/db 小鼠处理的 PTECs 中纯化了外泌体，并评估了它们对 MCs 和下游信号通路病理变化的影响。健康个体和 2 型糖尿病患者被纳入研究，以检查外泌体在临床应用中的作用。高葡萄糖刺激 PTECs 分泌外泌体 miR-92a-1-5p，其被肾小球 MCs 摄取，在体外和体内诱导肌成纤维细胞转分化 (MFT)。PTEC 释放的外泌体 92a-1-5p 降低了 reticulocalbin-3 的表达，通过下调 ER 稳态所必需的基因（包括钙网蛋白和中脑星形胶质细胞衍生的神经营养因子）导致内质网 (ER) 应激。用 miR-92a-1-5p 抑制剂治疗可改善患有 DN 的 db/db 小鼠的肾脏损伤。尿液 miR-92a-1-5p 可以预测 2 型糖尿病患者的肾损伤。PTEC 衍生的外泌体 miR-92a-1-5p 在体内和体外模型中调节肾脏微环境，从而改变 MC 中的 ER 应激和 MFT，导致 DN 进展。进一步阻断 miR-92a-1-5p 表观遗传调控网络可能是预防 DN 进展的潜在治疗策略。糖尿病肾病 (DN) 一直是全球终末期肾病的主要原因。外泌体在肾细胞的串扰中起主要作用，并进一步影响 DN 的发作或进展。本研究首先证明了近端肾小管上皮细胞（PTECs）和系膜细胞（MCs）之间通过外泌体传递的通讯。PTEC 释放的外泌体 92a-1-5p 通过 reticulocalbin-3 调节诱导 MC 中的内质网应激和上皮-间质转化。在用 miR-92a-1-5p 抑制剂治疗后，DN 小鼠的肾脏损伤得以挽救。此外，尿液外泌体 miR-92a-1-5p 可以预测 2 型糖尿病患者的 DN 进展。这些发现证明了外泌体 miR-92a-1-5p 对病理生理机制的影响及其在临床护理和 DN 预测中的潜在用途。