Kidney Internal Medicine, The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, 653100, Yunnan, China.
Int Urol Nephrol. 2024 Apr;56(4):1449-1463. doi: 10.1007/s11255-023-03819-3. Epub 2023 Oct 10.
The etiopathogenesis of diabetes nephropathy (DN) has not yet been fully clarified. Finding effective treatments to prevent renal failure in DN patients has become the main focus of research in recent years. Circular RNA (circRNA) has been shown to play a momentous role in DN progression. Based on this, we aimed to investigate the potential mechanism by which urine-derived stem cell (USC)-derived exosome circRNA ATG7 (Exo-ATG7) mediates DN progression.
Exosomes from USCs were isolated and identified. The DN rat model was established by intraperitoneally injecting 60 mg/kg streptozotocin. The protein expression levels were measured by Western blot and immunofluorescence. HE and Masson staining were used to evaluate renal injury, and the expression of related genes was detected by RT-qPCR.
CircRNA ATG7 was significantly downregulated in the DN rat model, and the extracellular vesicles of USCs improved renal function and reduced inflammation in DN rats. However, after knocking down the USCs-derived exosome circRNA ATG7, improvement and therapeutic effect on renal function in DN rats were lost. In addition, overexpression of ATG7 facilitated the switching of macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype both in vivo and in vitro. Mechanistically, upregulation of circRNA ATG7 expression can alleviate renal damage in DN rats. Importantly, the USCs-derived exosome circRNA ATG7 promotes macrophage M2 polarization by regulating the SOCS1/STAT3 signaling pathway through miR-4500. In addition, animal experiments also confirmed that after knocking down ATG7 in USC cells, the extracted exosome-treated DN rats could weaken the therapeutic effect of USC exosomes.
Our research results indicate that USC-derived exosomal circRNA ATG7 facilitates macrophage phenotype switching from M1 to M2 through the SOCS1/STAT3 signaling pathway mediated by miR-4500, thereby inhibiting DN progression.
糖尿病肾病（DN）的发病机制尚未完全阐明。寻找有效的治疗方法来防止 DN 患者的肾功能衰竭已成为近年来研究的主要焦点。环状 RNA（circRNA）在 DN 进展中发挥着重要作用。基于此，我们旨在研究尿源性干细胞（USC）衍生的外泌体 circRNA ATG7（Exo-ATG7）介导 DN 进展的潜在机制。
分离和鉴定 USCs 的外泌体。通过腹腔内注射 60mg/kg 链脲佐菌素建立 DN 大鼠模型。通过 Western blot 和免疫荧光法测量蛋白表达水平。HE 和 Masson 染色评估肾脏损伤，通过 RT-qPCR 检测相关基因的表达。
DN 大鼠模型中 circRNA ATG7 表达显著下调，USCs 的细胞外囊泡改善了 DN 大鼠的肾功能并减轻了炎症。然而，敲低 USCs 衍生的外泌体 circRNA ATG7 后，DN 大鼠肾功能的改善和治疗效果丧失。此外，ATG7 的过表达促进了体内和体外巨噬细胞从促炎 M1 表型向抗炎 M2 表型的转换。机制上，circRNA ATG7 的上调表达可以减轻 DN 大鼠的肾脏损伤。重要的是，USCs 衍生的外泌体 circRNA ATG7 通过调节 SOCS1/STAT3 信号通路，通过 miR-4500 促进巨噬细胞 M2 极化。此外，动物实验还证实，敲低 USC 细胞中的 ATG7 后，提取的外泌体处理的 DN 大鼠可以减弱 USC 外泌体的治疗效果。
我们的研究结果表明，USC 衍生的外泌体 circRNA ATG7 通过 miR-4500 介导的 SOCS1/STAT3 信号通路促进巨噬细胞从 M1 向 M2 表型转换，从而抑制 DN 的进展。
