Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells preserve mitochondrial functions and redox homeostasis in ischemia–reperfusion-induced acute kidney injury

Oct 31, 2025Biochimica et biophysica acta. General subjects

Vesicles from low-oxygen treated stem cells help protect energy and balance in sudden kidney injury

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Abstract

Hypoxia-preconditioned extracellular vesicles from adipose-derived mesenchymal stem cells may protect renal mitochondria during acute kidney injury.

Extracellular vesicles prevented tubular injury and inflammatory infiltration in a rat model of ischemia-reperfusion-induced acute kidney injury.
Treatment with extracellular vesicles preserved renal architecture following ischemia-reperfusion.
Extracellular vesicles enhanced the movement of a specific protein (Nrf2) into the cell nucleus and increased levels of another protein (HO-1) associated with antioxidant defenses.
Mitochondrial functions, including membrane potential and ATP synthesis, were maintained with extracellular vesicle treatment, though one component (complex II) showed vulnerability.
Proton leak responses were not affected by extracellular vesicle treatment.

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Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) remains a significant clinical challenge due to its rapid progression, limited therapeutic options, and high morbidity. Mitochondrial dysfunction is a critical component of AKI pathogenesis, contributing to oxidative stress, impaired bioenergetics, and tissue injury. Extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) have emerged as potential candidates for organ protection through the modulation of inflammatory and oxidative pathways. This study evaluated the effects of EV secreted by hypoxia-preconditioned adipose-derived MSC on mitochondrial function in a rat model of I/R-induced AKI. Wistar rats were assigned to four groups: SHAM, I/R, SHAM + EV, and I/R + EV. Hypoxia-preconditioned EV (2 × 10) or vehicle were administered subcapsularly 1 h prior to bilateral renal artery clamping (45 min ischemia, 1 h reperfusion). Histological analyses demonstrated that EV treatment effectively prevented tubular injury, inflammatory infiltration, and preserved renal architecture. EV enhanced Nrf2 nuclear translocation, upregulated HO-1 expression, and stabilized antioxidant defenses. Furthermore, EV preserved mitochondrial membrane potential, respiratory control ratio, ATP synthesis, and the abundance of electron transport chain complexes I, III, and IV, although complex II remained vulnerable. Proton leak responses were unaffected. These results demonstrate that hypoxia-preconditioned MSC-derived EV exert rapid protective effects on renal mitochondria and redox homeostasis during early reperfusion, offering a promising therapeutic strategy for AKI prevention in clinical scenarios such as transplantation and major cardiovascular surgeries. Further studies are needed to characterize the cargo of EV and their long-term outcomes. 9

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Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells preserve mitochondrial functions and redox homeostasis in ischemia–reperfusion-induced acute kidney injury

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