Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

Abstract

Autophagy is an important mechanism for cellular homeostasis and survival during pathologic stress conditions in the kidney, such as ischemia‐reperfusion (IR) injury. In this study, renal IR was induced in female C57BL/6 mice after melatonin administration. Renal function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity, autophagy changing, apoptosis levels, and autophagy‐associated intracellular signaling pathway were assessed to evaluate the impact of antecedent melatonin treatment on IR‐induced renal injury. The administration of melatonin resulted in significantly preserved renal function, and the protective effect was associated with ameliorated oxidative stress, limited pro‐inflammatory cytokine production, and neutrophil and macrophage infiltration. Moreover, autophagic flux was increased after melatonin administration while the apoptosis levels were decreased in the melatonin‐pretreated mice. Using TAK‐242 and CRX‐527, we confirmed that MyD88‐dependent TLR4 and MEK/ERK/mTORC1 signaling participated in melatonin‐induced autophagy in IR mice. Collectively, our results provide novel evidence that antecedent melatonin treatment provides protection for the kidney against IR injury by enhancing autophagy, as regulated by the TLR4/MyD88/MEK/ERK/mTORC1 signaling pathway. Therefore, melatonin preconditioning offers a potential therapeutic approach to prevent renal IR injury related to various clinical conditions.

Combined tacrolimus and melatonin effectively protected kidney against acute ischemia‐reperfusion injury

“…IR, ischemiareperfusion; ROS, oxidative stress; TLR4, toll-like receptor 4 was notably suppressed in IR animals after receiving Tac and Mel treatments and further notably suppressed after combined Tac-Mel treatment. Our findings, in addition to strengthening the finding of previous study, 27,41 could explained why the apoptotic and autophagic biomarkers were remarkably attenuated in IR animals after receiving the Tac-Mel treatment.…”

HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

“…HDAC6 binds to LC3 to mediate autophagy ( Peixoto et al, 2020 ). TLR4/MyD88/ERK signaling mediates Melatonin-induced autophagy ( Yang et al, 2020 ). HDAC6 binds to MyD88 and regulates autophagy ( Moreno-Gonzalo et al, 2017 ).…”

A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury

“…Thus, a temporary pharmacologic intervention to block TLRs during the acute phase of IRI would be an appropriate approach. Several compounds, such as eritoran, TAK-242, OPN301, melatonin, pituitary adenylate cyclase-activating polypeptide 38, and ODN2088-encapsulated nanoparticles, have been found to ameliorate renal IRI through TLR inhibition; however, none of these have been approved for kidney injury encountered in clinical practice [23][24][25][26][27][28]. In contrast to eritoran and TAK-242, which have selective specificity for TLR4, OPN301 for TLR2, and ODN2088-encapsulated nanoparticles for TLR9, we found that, in our prior in vitro study using immune cells, TIP1 exerts an inhibitory action on TLR1 through TLR9, with the exception of TLR5.…”