Ishiy Crysthiane Saveriano Rubiao Andre, Ormanji Milene Subtil, Maquigussa Edgar, Ribeiro Rosemara Silva, da Silva Novaes Antonio, Boim Mirian Aparecida
Renal Division, Department of Medicine-Federal University of São Paulo, São Paulo, Brazil.
Stem Cells Int. 2020 Oct 8;2020:8814574. doi: 10.1155/2020/8814574. eCollection 2020.
Chronic renal artery stenosis is considered one of the most common causes of renovascular hypertension (RH). Chronic hypoxia can lead to irreversible damage to renal tissue and to a progressive deterioration of renal function. We have previously shown that bone marrow-derived mesenchymal stem cells (BMSCs) improved renal parenchyma and function in a model of RH (2 kidneys, 1 clip model (2K-1C) in rats. Microvesicles (MVs) and exosomes (EXs) released by MSCs have been shown to induce effects similar to those induced by whole cells but with fewer side effects. In this study, we compared the effects of adipose-derived MSCs (ASCs) with those of the MVs and EXs released by ASCs on tissue inflammation and renal function in 2 K-1C rats.
Flow cytometry analysis showed that even after 15 days, ASCs were still detected in both kidneys. The expression of a stem cell homing marker (SDF1-) was increased in ASC-treated animals in both the stenotic and contralateral kidneys. Interestingly, SDF1- expression was also increased in MV- and EX-treated animals. A hypoxia marker (HIF1-) was upregulated in the stenotic kidney, and treatments with ASCs, MVs, and EXs were effective in reducing the expression of this marker. Stenotic animals showed a progressive increase in systolic blood pressure (SBP), while animals treated with ASCs, MVs, and EXs showed a stabilization of SBP, and this stabilization was similar among the different treatments. Stenotic animals developed significant proteinuria, which was reduced by ASCs and MVs but not by EXs. The increased expression of Col I and TGF in both kidneys was reduced by all the treatments, and these treatments also effectively increased the expression of the anti-inflammatory cytokine IL-10 in both kidneys; however, only ASCs were able to reduce the overexpression of the proinflammatory cytokine IL-1 in both kidneys of 2K-1C animals.
The results of this study demonstrated that the EVs released by ASCs produced beneficial results but with lower efficacy than whole cells. ASCs produced stronger effects in this model of renal chronic hypoxia, and the use of EVs instead of whole cells should be evaluated depending on the parameter to be corrected.
慢性肾动脉狭窄被认为是肾血管性高血压（RH）最常见的病因之一。慢性缺氧可导致肾组织不可逆转的损伤以及肾功能的进行性恶化。我们之前已经证明，在大鼠肾血管性高血压模型（双肾一夹模型，2K-1C）中，骨髓间充质干细胞（BMSCs）可改善肾实质和肾功能。已证明，间充质干细胞释放的微泡（MVs）和外泌体（EXs）可诱导产生与全细胞相似的效应，但副作用较少。在本研究中，我们比较了脂肪来源的间充质干细胞（ASCs）及其释放的MVs和EXs对2K-1C大鼠组织炎症和肾功能的影响。
流式细胞术分析显示，即使在15天后，仍可在双肾中检测到ASCs。在接受ASC治疗的动物的狭窄肾和对侧肾中，干细胞归巢标志物（SDF1-）的表达均增加。有趣的是，在接受MV和EX治疗的动物中，SDF1-表达也增加。狭窄肾中缺氧标志物（HIF1-）上调，而ASC、MV和EX治疗可有效降低该标志物的表达。狭窄组动物的收缩压（SBP）逐渐升高，而接受ASC、MV和EX治疗的动物SBP稳定，且不同治疗组之间的这种稳定情况相似。狭窄组动物出现明显蛋白尿，ASC和MV治疗可使其减少，但EX治疗无效。所有治疗均降低了双肾中I型胶原（Col I）和转化生长因子（TGF）的表达增加，且这些治疗还有效增加了双肾中抗炎细胞因子白细胞介素-10（IL-10）的表达；然而，只有ASC能够降低2K-1C动物双肾中促炎细胞因子白细胞介素-1（IL-1）的过表达。
本研究结果表明，ASC释放的细胞外囊泡（EVs）产生了有益效果，但效力低于全细胞。在这个肾慢性缺氧模型中，ASC产生的效果更强，应根据要纠正的参数来评估使用EVs而非全细胞的情况。
