melitten and Acute-Kidney-Injury

Sepsis-related acute kidney injury (AKI) is a worldwide health problem, and its pathogenesis involves multiple pathways. Lipopolysaccharide (LPS) is an endotoxin that induces systemic inflammatory responses. Melittin, a main constituent of bee venom, exerts several biological activities such as antioxidant, anti-inflammatory, and antiapoptotic actions. However, whether melittin protects against endotoxin-induced AKI remains undetermined. Here, we aimed to examine the potential action of melittin on LPS-induced renal injury and explore the mechanisms. We showed that acute renal failure and structural damage after injection of LPS were markedly attenuated by administration of melittin. The peptide also suppressed expression of markers of direct tubular damage in kidneys of the LPS-treated mice. Mechanistically, melittin reduced systemic and renal levels of cytokines and inhibited renal accumulation of immune cells with concomitant suppression of nuclear factor kappa-B pathway. Increased amounts of lipid peroxidation products after LPS treatment were largely decreased by melittin. Additionally, the peptide decreased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and enhanced nuclear factor erythroid-2-related factor 2-mediated antioxidant defenses. Moreover, melittin inhibited apoptotic and necroptotic cell death after LPS treatment. Lastly, we showed that melittin improved the survival rate of LPS-injected mice. These results suggest that melittin ameliorates endotoxin-induced AKI and mortality through inhibiting inflammation, oxidative injury, and apoptotic and necroptotic death of tubular epithelial cells.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cell Death; Endotoxins; Inflammation; Male; Melitten; Mice; Mice, Inbred C57BL; Oxidative Stress; Protective Agents

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.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Bee Venoms; Cisplatin; Cytokines; Disease Models, Animal; Inflammation Mediators; Kidney; Macrophage Activation; Macrophages; Male; Melitten; Mice; Phenotype

To establish a goat model of melittin induced acute kidney injury (AKI), and to evaluate the therapeutic effect of continuous veno-venus heamofiltration (CVVH) in melittin- induced AKI.. Twelve male goats were randomized into three groups: control group, melittin induced AKI group (melittin group), and CVVH intervention group (CVVH group). The AKI goat model was established by the injection of melittin via the auricular vein for four times in 48 h to reach a total dose of 0.5 mg/kg, then serum creatinine (Cr) and creatine kinase (CK) were tested every 6 h and urine output was record each hour. AKI was diagnosed when Cr level increased to the double value of control group, or the urine output decreased to less than 0. 5 mL/(kg x h) in 6 h. After the diagnosis of AKI, the animals in CVVH group received CVVH treatment for 12 h. At the end, the goats in all groups were sacrificed by anesthesia and kidney tissue samples were collected. Light microscopy and telectron microscopy observation were performed. Apoptosis was detected by immunohistochemistry and TUNEL technique.. AKI was successfully induced by melittin in the goats. The Cr level in control group was (43.95 +/- 1.59) micromol/L, while (100.75 +/- 7.87) micromol/L in AKI group and (102.10 +/- 5.06) micromol/L in CVVH group. Cr level was lowered significantly after CVVH treatment [(45.02 +/- 2.41) micromol/L in control group vs. (108.60 +/- 9.40) micromol/L in AKI group vs. (64.13 +/- 5.82) micromol/L in CVVH group, P < 0.001]. Swelling and reduction of mitochondrial crests in AKI group were more obvious than those in CVVH group. Expression of caspase-3 and apoptosis cells percentage of renal tubules in AKI group were significantly higher than those in CVVH group.. Melittin induced AKI model could be established in goats. CVVH could alleviate melittin induced AKI, probably in the mechanism to reduce the apoptosis of renal tubular cells.

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Goats; Kidney; Kidney Function Tests; Male; Melitten; Renal Replacement Therapy