Melatonin attenuates ischemia-reperfusion-induced acute kidney injury by regulating abnormal autophagy and pyroptosis through SIRT1-mediated p53 deacetylation

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-06-24 DOI:10.1016/j.intimp.2025.115092

Chen Sun , Jia Liu , Hongjun Li , Youyou Yan

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引用次数: 0

Abstract

Ischemia-reperfusion (IR) injury is the leading cause of acute kidney injury (AKI), leading to deteriorated kidney function and high mortality. However, there are still no potent medications for IR-induced AKI. Pyroptosis is a type of inflammatory cell death that plays a significant role in IR-induced AKI, and inhibiting pyroptosis might be a promising therapeutic strategy. Melatonin has been reported to protect against IR-induced AKI and inhibit pyroptosis in various diseases. Moreover, Autophagy inhibits pyroptosis, which is affected by melatonin via up-regulation of SIRT1. SIRT1 mediates the p53 deacetylation, which can promote autophagy. However, the role of melatonin in regulating autophagy and pyroptosis through the SIRT1/p53 pathway in lessening IR-induced AKI is yet to be elucidated. Our data showed that melatonin significantly reduced IR or OGD/R-induced renal damage by inhibiting pyroptosis and promoting autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) countered the protective effect of melatonin on inhibiting OGD/R-induced pyroptosis, ROS, and lactate dehydrogenase (LDH) productions in HK2 cells. In addition, SIRT1 was decreased by IR or OGD/R stimulation, which was significantly alleviated by melatonin treatment. Mechanistically, melatonin alleviates IR-induced AKI by activating autophagy to inhibit pyroptosis through SIRT1-mediated p53 deacetylation and nuclear translocation. Our data demonstrated the mechanism and potential therapeutics of melatonin in IR-induced AKI.

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褪黑素通过sirt1介导的p53去乙酰化调节异常自噬和焦亡，减轻缺血再灌注诱导的急性肾损伤

缺血再灌注（IR）损伤是急性肾损伤（AKI）的主要原因，可导致肾功能恶化和高死亡率。然而，目前仍没有有效的药物治疗ir诱导的AKI。焦亡是一种炎症细胞死亡，在ir诱导的AKI中起着重要作用，抑制焦亡可能是一种很有前景的治疗策略。据报道，褪黑素可以预防ir诱导的AKI，并抑制各种疾病的焦亡。此外，自噬抑制焦亡，褪黑素通过上调SIRT1影响焦亡。SIRT1介导p53去乙酰化，促进自噬。然而，褪黑素通过SIRT1/p53通路调节自噬和焦亡在减轻ir诱导AKI中的作用尚不清楚。我们的数据显示，褪黑素通过抑制焦亡和促进自噬，显著减少IR或OGD/ r诱导的肾损伤。3-甲基腺嘌呤（3-MA）对HK2细胞自噬的抑制作用抵消了褪黑素抑制OGD/ r诱导的焦亡、ROS和乳酸脱氢酶（LDH）产生的保护作用。此外，IR或OGD/R刺激可降低SIRT1，褪黑激素治疗可显著缓解SIRT1。机制上，褪黑素通过sirt1介导的p53去乙酰化和核易位，激活自噬抑制焦亡，从而减轻ir诱导的AKI。我们的数据证明了褪黑素在ir诱导的AKI中的作用机制和潜在的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.