Melittin Ameliorates Endotoxin-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Cell Death in Mice.

Jung-Yeon Kim,Jaechan Leem,Hyo-Lim Hong,Patricia Morales

doi:10.1155/2021/8843051

Abstract

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.

Highlights

Sepsis is a serious medical condition triggered by abnormal immune responses to infection and remains a main global cause of death in hospitals [1]
Primary antibodies against inhibitor κB-α (IκBα), p-IκB-α, nuclear factor-κB (NF-κB) p65, p-NF-κB p65, cleaved poly(ADP-ribose) polymerase-1 (PARP-1), cleaved caspase-3, p53, receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, mixed-lineage kinase domain-like protein (MLKL), p-MLKL, or glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were obtained from Cell Signaling (Danvers, MA, USA)
hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining showed that LPS-injected group (LPS)-injected mice displayed histopathological alterations, including tubular dilatation and swelling of tubular epithelial cells (Figures 1(c) and 1(d))

Summary

Introduction

Sepsis is a serious medical condition triggered by abnormal immune responses to infection and remains a main global cause of death in hospitals [1]. Standard therapy for patients suffering from sepsis-related renal injury includes rapid administration of antibiotics and avoidance of hypotension through adequate fluid resuscitation or use of vasopressors [3]. Pathogen-associated molecular patterns (PAMPs) are produced by microorganisms and are detected by pattern recognition receptors. During sepsis, they are released into blood circulation [3]. Among PAMPs, lipopolysaccharide (LPS) is an endotoxin produced by gram-negative bacteria. This inflammatory mediator stimulates many different types of cells including renal tubular epithelial cells and immune cells through interacting with Toll-like receptors (TLRs), resulting in the induction of oxidative stress, inflammation, and cell death [3,4,5]

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