Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF‐kB and apoptosis after experimental kidney transplantation

Abstract

Free radicals are involved in pathophysiology of ischemia/reperfusion injury (IRI). Melatonin is a potent scavenger of reactive oxygen and nitrogen species. Thus, this study was designed to elucidate its effects in a model of rat kidney transplantation. Twenty Lewis rats were randomly divided into 2 groups (n = 10 animals each). Melatonin (50 mg/kg BW) dissolved in 5 mL milk was given to one group via gavage 2 hr before left donor nephrectomy. Controls were given the same volume of milk only. Kidney grafts were then transplanted into bilaterally nephrectomized syngeneic recipients after 24 hr of cold storage in Histidine-Tryptophan-Ketoglutarate solution. Both graft function and injury were assessed after transplantation through serum levels of blood urea nitrogen (BUN), creatinine, transaminases, and lactate dehydrogenase (LDH). Biopsies were taken to evaluate tubular damage, the enzymatic activity of superoxide dismutase (SOD) and lipid hydroperoxide (LPO), and the expression of NF-kBp65, inducible nitric oxide synthase (iNOS), caspase-3 as indices of oxidative stress, necrosis, and apoptosis, respectively. Melatonin improved survival (P < 0.01) while decreasing BUN, creatinine, transaminases, and LDH values up to 39-71% (P < 0.05). Melatonin significantly reduced the histological index for tubular damage, induced tissue enzymatic activity of SOD while reducing LPO. At the same time, melatonin down-regulated the expression of NF-kBp65, iNOS, and caspase-3. In conclusion, donor preconditioning with melatonin protected kidney donor grafts from IRI-induced renal dysfunction and tubular injury most likely through its anti-oxidative, anti-apoptotic and NF-kB inhibitory capacity.

Melatonin inhibits IL1β-induced MMP9 expression and activity in human umbilical vein endothelial cells by suppressing NF-κB activation

“…MMP9 is activated by reactive oxygen species and its expression is likely to be regulated by oxidative stress (Rajagopalan et al 1996, Mori et al 2004, Pustovrh et al 2005. Studies in the literature indicate that melatonin significantly inhibits the translocation and binding of NF-kB to DNA in rat spleen and downregulates the expression of NF-kB/p65 in the pathophysiology of ischemia/reperfusion injury in a model of rat kidney transplantation (Chuang et al 1996, Li et al 2009). We observed that melatonin inhibited the nuclear translocation of p65 in IL1b-treated HUVECs and downregulated p65 and MMP9 proteins expression.…”

Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats

“…Melatonin, a pineal secretory product, reduces the IRinduced brain, 12 heart, 13 kidney, 14,15 and liver 16 damages in rats. These effects of melatonin are related with scavenging of a variety of toxic oxygen and nitrogen-based reactants and stimulation of antioxidative enzymes.…”

Evaluation of antithrombotic and anti-ischemic effects of morinda citrifolia in renal autotransplantation in rats

“…Fruit juice of Morinda citrifolia is a well-known health drink and has various pharmacological properties including antioxidant and anti-inflammatory effects (5,6,8,11,15). On the other side, very few studies have been made on antiischemic effect of Morinda citrifolia and those studies related to the effects on brain damage associated with IRI (7,9).…”