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SETDB1 通过靶向 SESN2 调节肾缺血再灌注损伤中的线粒体损伤和氧化应激。

SETDB1 targeting SESN2 regulates mitochondrial damage and oxidative stress in renal ischemia-reperfusion injury.

机构信息

Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

出版信息

BMC Biol. 2024 Oct 23;22(1):246. doi: 10.1186/s12915-024-02048-z.

DOI:10.1186/s12915-024-02048-z
PMID:39443993
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11515507/
Abstract

BACKGROUND

The role of histone methyltransferase SETDB1 in renal ischemia-reperfusion (I/R) injury has not been explored yet. This study aims to investigate the potential mechanism of SETDB1 in regulating renal I/R injury and its impact on mitochondrial damage and oxidative stress.

METHODS

The in vivo model of renal I/R in mice and the in vitro model of hypoxia/reoxygenation (H/R) in human renal tubular epithelial cells (HK-2) were constructed to detect the expression of SETDB1. Next, the specific inhibitor (R,R)-59 and knockdown viruses were used to inhibit SETDB1 and verify its effects on mitochondrial damage and oxidative stress. Chromatin immunoprecipitation (ChIP) and coimmunoprecipitation (CoIP) were implemented to explore the in-depth mechanism of SETDB1 regulating renal I/R injury.

RESULTS

The study found that SETDB1 had a regulatory role in mitochondrial damage and oxidative stress during renal I/R injury. Notably, SESN2 was identified as a target of SETDB1, and its expression was under the influence of SETDB1. Besides, SESN2 mediated the regulation of SETDB1 on renal I/R injury. Through deeper mechanistic studies, we uncovered that SETDB1 collaborates with heterochromatin HP1β, facilitating the labeling of H3K9me3 on the SESN2 promoter and impeding SESN2 expression.

CONCLUSIONS

The SETDB1/HP1β-SESN2 axis emerges as a potential therapeutic strategy for mitigating renal I/R injury.

摘要

背景

组蛋白甲基转移酶 SETDB1 在肾缺血再灌注（I/R）损伤中的作用尚未被探索。本研究旨在探讨 SETDB1 调节肾 I/R 损伤的潜在机制及其对线粒体损伤和氧化应激的影响。

方法

构建了小鼠肾 I/R 的体内模型和人肾小管上皮细胞（HK-2）缺氧/复氧（H/R）的体外模型，以检测 SETDB1 的表达。接下来，使用特异性抑制剂（R,R）-59 和敲低病毒抑制 SETDB1，并验证其对线粒体损伤和氧化应激的影响。实施染色质免疫沉淀（ChIP）和共免疫沉淀（CoIP）实验，以探索 SETDB1 调节肾 I/R 损伤的深入机制。

结果

研究发现，SETDB1 在肾 I/R 损伤过程中对线粒体损伤和氧化应激具有调节作用。值得注意的是，SESN2 被鉴定为 SETDB1 的靶标，其表达受 SETDB1 的影响。此外，SESN2 介导了 SETDB1 对肾 I/R 损伤的调节。通过更深入的机制研究，我们揭示了 SETDB1 与异染色质 HP1β 合作，促进 H3K9me3 在 SESN2 启动子上的标记，并抑制 SESN2 的表达。

结论

SETDB1/HP1β-SESN2 轴可能成为减轻肾 I/R 损伤的潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/733e60970f98/12915_2024_2048_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/733e60970f98/12915_2024_2048_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/59fe9807b23d/12915_2024_2048_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/4a7334cbd632/12915_2024_2048_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/464172e65471/12915_2024_2048_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/a90234193c44/12915_2024_2048_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/ca9ca2c87914/12915_2024_2048_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/bac3cd643e8e/12915_2024_2048_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2925/11515507/733e60970f98/12915_2024_2048_Fig9_HTML.jpg

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Histochem Cell Biol. 2024 Apr;161(4):325-336. doi: 10.1007/s00418-023-02263-9. Epub 2024 Jan 13.
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Sentrin-specific protease 1 maintains mitochondrial homeostasis through targeting the deSUMOylation of sirtuin-3 to alleviate oxidative damage induced by hepatic ischemia/reperfusion.特定位点蛋白酶 1 通过靶向沉默调节蛋白 3 的去 SUMO 化作用维持线粒体稳态，从而减轻肝缺血/再灌注引起的氧化损伤。
Free Radic Biol Med. 2024 Jan;210:378-389. doi: 10.1016/j.freeradbiomed.2023.11.040. Epub 2023 Dec 3.
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