Abstract
Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O2•−) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administered during reperfusion can suppress the exacerbated mitochondrial O2•− formation after I/R. We used Wistar rats subjected to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R + EVs group) or saline (I/R group) in the kidney subcapsular space. The third group consisted of false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and used immediately. Amplex Red™ was used to measure mitochondrial O2•− formation and MitoTracker™ Orange to evaluate inner mitochondrial membrane potential (Δψ). In vitro studies were carried out on human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxic conditions. Administration of EVs restored O2•− formation to SHAM levels in all mitochondrial functional conditions. The gene expression of catalase and superoxide dismutase-1 remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs favor long-term recovery of renal structures and functions after I/R rely on a decrease of mitochondrial O2•− formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.
Highlights
Acute kidney injury (AKI) is one of the most severe systemic syndromes in internal medicine, with significant mortality rates, especially in intensive-care units (ICUs), where it accounts for more than 15% of the hospitalized patients [1] and 50% of those that are critically ill [2]
Considering that the effect of extracellular vesicles (EVs) secreted by adipose mesenchymal stromal cells (MSC), following subcapsular administration at the beginning of reperfusion, prevented or diminished tissular and functional damage 3 days after ischemia followed by reperfusion (I/R) [10], the present study aimed to investigate the early
2.1.2.Characterization of Extracellular Vesicles Secreted by Adipose Tissue Mesenchymal Stromal
Summary
Acute kidney injury (AKI) is one of the most severe systemic syndromes in internal medicine, with significant mortality rates, especially in intensive-care units (ICUs), where it accounts for more than 15% of the hospitalized patients [1] and 50% of those that are critically ill [2]. In the last few decades, replacements started focusing on cell therapies to prevent or slow the progression from AKI to chronic kidney disease (CKD). Expectations were centered on renal resident adult stem cells [6,7], but this hope was almost totally dissipated when the existence of such cells was challenged [8,9]. The use of progenitor cells is intensely focused on mesenchymal stromal cells (MSC) and the vesicles they secrete to the extracellular milieu (EVs). We demonstrated that EVs secreted by adipose
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