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-1 beta, 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.