Dexmedetomidine ameliorates acute kidney injury by regulating mitochondrial dynamics via the α2-AR/SIRT1/PGC-1α pathway activation in rats.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2024-10-25 DOI:10.1186/s10020-024-00964-y

Shuai Zhang, Xiujing Feng, Guiyan Yang, Haoyang Tan, Xin Cheng, Qichao Tang, Haotian Yang, Yuan Zhao, Xuanpan Ding, Siyao Li, Xinyi Dou, Junfeng Li, Huijie Kang, Xingxing Li, Yaxin Ji, Qingdian Hou, Qiuyue An, Hao Fang, Honggang Fan

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引用次数: 0

Abstract

Background: Sepsis-associated acute kidney injury (AKI) is a serious complication of systemic infection with high morbidity and mortality in patients. However, no effective drugs are available for AKI treatment. Dexmedetomidine (DEX) is an alpha 2 adrenal receptor agonist with antioxidant and anti-apoptotic effects. This study aimed to investigate the therapeutic effects of DEX on sepsis-associated AKI and to elucidate the role of mitochondrial dynamics during this process.

Methods: A lipopolysaccharide (LPS)-induced AKI rat model and an NRK-52E cell model were used in the study. This study investigated the effects of DEX on sepsis-associated AKI and the molecular mechanisms using histologic assessment, biochemical analyses, ultrastructural observation, western blotting, immunofluorescence, immunohistochemistry, qRT-PCR, flow cytometry, and si-mRNA transfection.

Results: In rats, the results showed that administration of DEX protected kidney structure and function from LPS-induced septic AKI. In addition, we found that DEX upregulated the α2-AR/SIRT1/PGC-1α pathway, protected mitochondrial structure and function, and decreased oxidative stress and apoptosis compared to the LPS group. In NRK-52E cells, DEX regulated the mitochondrial dynamic balance by preventing intracellular Ca²⁺ overloading and activating CaMKII.

Conclusions: DEX ameliorated septic AKI by reducing oxidative stress and apoptosis in addition to modulating mitochondrial dynamics via upregulation of the α2-AR/SIRT1/PGC-1α pathway. This is a confirmatory study about DEX pre-treatment to ameliorate septic AKI. Our research reveals a novel mechanistic molecular pathway by which DEX provides nephroprotection.

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右美托咪定通过激活α2-AR/SIRT1/PGC-1α途径调节大鼠线粒体动力学，从而改善急性肾损伤。

背景：败血症相关急性肾损伤（AKI）是全身感染的严重并发症，发病率和死亡率都很高。然而，目前尚无治疗急性肾损伤的有效药物。右美托咪定（DEX）是一种α2肾上腺受体激动剂，具有抗氧化和抗细胞凋亡作用。本研究旨在探讨DEX对脓毒症相关性AKI的治疗效果，并阐明线粒体动力学在这一过程中的作用：研究采用了脂多糖（LPS）诱导的 AKI 大鼠模型和 NRK-52E 细胞模型。本研究采用组织学评估、生化分析、超微结构观察、Western印迹、免疫荧光、免疫组织化学、qRT-PCR、流式细胞术和si-mRNA转染等方法研究了DEX对脓毒症相关AKI的影响及其分子机制：结果：研究结果表明，DEX能保护大鼠的肾脏结构和功能，使其免受LPS诱导的脓毒性AKI的影响。此外，我们还发现与 LPS 组相比，DEX 上调了 α2-AR/SIRT1/PGC-1α 通路，保护了线粒体结构和功能，降低了氧化应激和细胞凋亡。在NRK-52E细胞中，DEX通过防止细胞内Ca2+超载和激活CaMKII来调节线粒体的动态平衡：结论：DEX除了通过上调α2-AR/SIRT1/PGC-1α通路调节线粒体动态平衡外，还能减少氧化应激和细胞凋亡，从而改善脓毒性AKI。这是一项关于DEX预处理改善脓毒症AKI的确证研究。我们的研究揭示了DEX提供肾脏保护的新机制分子途径。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.