Bee Venom Melittin Protects against Cisplatin-Induced Acute Kidney Injury in Mice via the Regulation of M2 Macrophage Activation

Abstract

Inflammation is an essential biological response that eliminates pathogenic bacteria and repairs tissue after injury. Acute kidney injury (AKI) is associated with systemic and intrarenal inflammation as the inflammatory process decreases renal function and promotes progression to advanced chronic kidney disease. Macrophages are key mediators of the inflammatory response; their activation influences the immune system and may have various effects. Classically activated type I macrophages (M1) produce a variety of pro-inflammatory cytokines at the lesion site. However, anti-inflammatory type II macrophages (M2) are alternatively activated upon exposure to anti-inflammatory cytokines and are associated with wound healing and tissue repair following AKI. Here, we used melittin from bee venom to enhance the polarization of M2 macrophages and promote renal recovery after AKI. Melittin was administered to mice intraperitoneally for 5 days at various concentrations (10, 50, and 100 µg/kg); serum creatinine and blood urea nitrogen (BUN) levels were analyzed 72 h after cisplatin administration to confirm renal dysfunction. Melittin inhibited the cisplatin-induced increase in creatinine and BUN, an indicator of renal dysfunction. The expression of M1 markers (CD16/32) decreased significantly, whereas that of M2 markers (CD206, Arg1nase I) increased after melittin administration. Consistently, tubular necrosis was substantially reduced in melittin-treated mice. Thus, melittin alleviates cisplatin-induced AKI by regulating M2 macrophage expression.

Bee Venom and Its Sub-Components: Characterization, Pharmacology, and Therapeutics

“…A total of 11 studies were published. Three reviews provided a good overview of the therapeutic effect of bee venom [ 6 , 7 , 8 ], and eight original research articles focused on bee venom, melittin, PLA 2 , and apamin [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…Third, Zorila et al [ 16 ] used spectral analysis of Laurdan fluorescence to demonstrate that melittin could induce local order changes in artificial and biological membranes. Finally, Kim et al [ 12 ] examined the role of melittin in cisplatin-induced acute kidney injury and showed that intraperitoneal administration of different doses of melittin could inhibit cisplatin-induced increase in creatinine and blood urea nitrogen by regulating M2 macrophage expression.…”

Bee venom acupuncture therapy ameliorates neuroinflammatory alterations in a pilocarpine-induced epilepticus model

“…In addition to PLA2, as an active component of BV, modulating Treg cells in some neuroin ammatory disease models, including Alzheimer disease (Baek et al, 2018) and Parkinson's disease (Chung et al, 2012) models and therefore BV can rescue dopaminergic neurons from injury or neurodegeneration, melittin can modify the release and production of different cytokines; it was found to increase levels of the antiin ammatory cytokine IL-10 and prevent the release of the proin ammatory cytokines IL-6 and IL-1β (Kim et al, 2020). In addition, BV restores the brain's neurochemistry and ameliorates all changes in neuroin ammatory biomarkers in rotenone-induced Parkinson's disease (Khalil et al, 2015).…”

Acute kidney injury caused by venomous animals: inflammatory mechanisms

“…Nephrotoxicity from snake venom can have several origins such as impaired perfusion due to intravascular coagulation, direct action of venom cytotoxic components on renal structures, and either hemoglobin or myoglobin deposits onto proximal and distal renal tubule. Another possible renal failure cause refers to cardiotoxins and nephrotoxic components in these animals venom [ 35 , 37 ]. Some studies evaluated dissimilar venom fractions in different animals and their findings point to changes in renal hemodynamics as well as proximal and distal renal tubular degeneration [ 33 , 35 ].…”

“…However, there is clinical and experimental evidence of venoms from different snakes that cause acute kidney damage [4,[33][34][35][36]. While envenoming refers to components causing neurotoxic manifestations, other other systemic manifestations are equally present [37], whose pathways are reviewed in [38].…”