Renal, but not platelet or skin, extracellular vesicles decrease oxidative stress, enhance nascent peptide synthesis, and protect from ischemic renal injury.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-08-01 Epub Date: 2023-06-15 DOI:10.1152/ajprenal.00321.2022
Jesus H Dominguez, Danhui Xie, K J Kelly
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Abstract

Acute kidney injury (AKI) is deadly and expensive, and specific, effective therapy remains a large unmet need. We have demonstrated the beneficial effects of transplanted adult tubular cells and extracellular vesicles (EVs; exosomes) derived from those renal cells on experimental ischemic AKI, even when administered after renal failure is established. To further examine the mechanisms of benefit with renal EVs, we tested the hypothesis that EVs from other epithelia or platelets (a rich source of EVs) might be protective, using a well-characterized ischemia-reperfusion model. When given after renal failure was present, renal EVs, but not those from skin or platelets, markedly improved renal function and histology. The differential effects allowed us to examine the mechanisms of benefit with renal EVs. We found significant decreases in oxidative stress postischemia in the renal EV-treated group with preservation of renal superoxide dismutase and catalase as well as increases in anti-inflammatory interleukin-10. In addition, we propose a novel mechanism of benefit: renal EVs enhanced nascent peptide synthesis following hypoxia in cells and in postischemic kidneys. Although EVs have been used therapeutically, these results serve as "proof of principle" to examine the mechanisms of injury and protection.NEW & NOTEWORTHY Acute kidney injury is common and deadly, yet the only approved treatment is dialysis. Thus, a better understanding of injury mechanisms and potential therapies is needed. We found that organ-specific, but not extrarenal, extracellular vesicles improved renal function and structure postischemia when given after renal failure occurred. Oxidative stress was decreased and anti-inflammatory interleukin-10 increased with renal, but not skin or platelet, exosomes. We also propose enhanced nascent peptide synthesis as a novel protective mechanism.

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肾脏(而非血小板或皮肤)细胞外囊泡可降低氧化应激,促进新生肽的合成,保护肾脏免受缺血性损伤。
急性肾损伤(AKI)是一种致命且昂贵的疾病,而特异、有效的治疗方法仍是一大未满足的需求。我们已经证明,移植的成人肾小管细胞和从这些肾细胞中提取的细胞外囊泡(EVs;外泌体)对实验性缺血性 AKI 有益,即使是在肾衰竭发生后给药也是如此。为了进一步研究肾脏细胞外小泡的获益机制,我们利用一个特征明确的缺血再灌注模型,测试了来自其他上皮细胞或血小板(一种丰富的细胞外小泡来源)的细胞外小泡可能具有保护作用的假设。当肾功能衰竭出现后给予肾脏 EVs,而不是来自皮肤或血小板的 EVs,可明显改善肾功能和组织学。由于效果不同,我们得以研究肾脏 EVs 的获益机制。我们发现,肾脏 EV 治疗组缺血后氧化应激明显减少,肾脏超氧化物歧化酶和过氧化氢酶得到保护,抗炎性白细胞介素-10 增加。此外,我们还提出了一种新的获益机制:肾脏 EVs 可增强细胞缺氧后和缺血后肾脏中新生肽的合成。虽然 EVs 已被用于治疗,但这些结果可作为研究损伤和保护机制的 "原理证明"。因此,需要更好地了解损伤机制和潜在疗法。我们发现,在肾功能衰竭发生后给予器官特异性细胞外囊泡能改善缺血后的肾功能和结构,但不能改善肾外囊泡。肾脏外泌体而非皮肤或血小板外泌体可降低氧化应激,增加抗炎白细胞介素-10。我们还提出,增强新生肽合成是一种新的保护机制。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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