Renal, but Not Platelet or Skin, Extracellular Vesicles Decrease Oxidative Stress, Enhance Nascent Peptide Synthesis, and Protect from Ischemic Renal Injury

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. 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.