Combination therapy with melatonin, stem cells and extracellular vesicles is effective in limiting renal ischemia–reperfusion injury in a rat model

Objective To evaluate the therapeutic value of melatonin, mesenchymal stem cells and their extracellular vesicles, exosomes, on renal ischemia–reperfusion. Methods Female albino rats ( n = 64) were divided into eight groups ( n = 8 per group): control, sham (only laparotomy), renal ischemia–reperfusion (renal ischemia–reperfusion + phosphate‐buffered saline), melatonin (renal ischemia–reperfusion + melatonin), mesenchymal stem cells (renal ischemia–reperfusion + mesenchymal stem cells), exosomes (renal ischemia–reperfusion + exosomes), melatonin + mesenchymal stem cells (renal ischemia–reperfusion + melatonin + mesenchymal stem cells) and melatonin + exosomes (renal ischemia–reperfusion + melatonin + exosomes). After the establishment of the renal ischemia–reperfusion model, rats in each group were bilaterally injected once with either mesenchymal stem cells or exosomes in both renal arteries during reperfusion. Results Notable improvement of renal ischemia–reperfusion was obtained after different treatments, as evidenced by a lower histopathological score of kidney injury; decreased serum levels of urea, creatinine and retinol‐binding protein; reduced lipid peroxidation marker malondialdehyde; increased superoxide dismutase and catalase activities; reduced apoptosis (lower DNA damage and B‐cell lymphoma 2‐associated X protein, and higher B‐cell lymphoma 2 genes/proteins); and inhibition of kidney inflammatory and damage markers (tumor necrosis alpha, interleukin‐1β, nuclear factor kappa B, kidney injury molecule‐1, IL‐18 , matrix metalloproteinase 9, neutrophil gelatinase‐associated lipocalin). The improvement order was (highest to lowest): melatonin + exosomes, melatonin + mesenchymal stem cells, exosomes, mesenchymal stem cells and melatonin group. Conclusions Our data suggest a potential therapeutic effect of combined therapy with melatonin, mesenchymal stem cells and their exosomes to minimize renal ischemia–reperfusion injury in rats.