Zhu Fengming, Chong Lee Shin Octavia L S, Pei Guangchang, Hu Zhizhi, Yang Juan, Zhu Han, Wang Meng, Mou Jingyi, Sun Jie, Wang Yuxi, Yang Qian, Zhao Zhi, Xu Huzi, Gao Hui, Yao Weiqi, Luo Xiao, Liao Wenhui, Xu Gang, Zeng Rui, Yao Ying
Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
Oncotarget. 2017 Aug 7;8(41):70707-70726. doi: 10.18632/oncotarget.19979. eCollection 2017 Sep 19.
Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling , but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.
急性肾损伤（AKI）使患者发展为进行性慢性肾脏病（CKD）的风险增加，然而有效的治疗方法仍然难以捉摸。本研究旨在探讨人脂肪来源的间充质干细胞（hAD-MSCs）在预防AKI向CKD转变中的治疗效果，并阐明肾发育过程中的关键转录因子Sox9在此过程中的作用。对C57BL/6小鼠进行单侧肾缺血/再灌注（I/R），部分小鼠接受hAD-MSC治疗。我们发现，hAD-MSC治疗上调了肾小管Sox9的表达，促进了肾小管再生，减轻了AKI，并缓解了随后的肾纤维化。然而，抑制hAD-MSCs释放外泌体的药物消除了这些有益作用。同样，Sox9抑制剂也逆转了这些保护作用。此外，我们证实hAD-MSCs通过外泌体转运激活肾小管Sox9，并防止TGF-β1诱导的肾小管上皮细胞（TECs）向促纤维化表型转化，但这些细胞并未抑制TGF-β1诱导的成纤维细胞向肌成纤维细胞的转变。抑制hAD-MSCs释放外泌体或TECs中Sox9的表达可逆转这些抗纤维化作用。总之，hAD-MSCs通过外泌体，依赖肾小管上皮细胞激活Sox9来减轻AKI向CKD的转变。
