Hesperetin ameliorates mitochondrial dysfunction in acute kidney injury by mediating autophagy and inhibiting the cGAS-STING pathway

IF 2.2 4区 生物学 Q3 CELL BIOLOGY
Pei Cao, Wan Zhu, Deng Li, JiGang Zhang, Xing Feng
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引用次数: 0

Abstract

Cisplatin-induced acute kidney injury (AKI) represents a severe complication of anticancer therapy with no effective clinical interventions, frequently necessitating chemotherapy dose reduction or discontinuation. Natural products have emerged as promising therapeutic candidates against cisplatin nephrotoxicity due to their multi-target mechanisms, pleiotropic effects, and low resistance potential. This study explored the therapeutic potential of hesperetin (Hes) in ameliorating mitochondrial dysfunction during AKI through coordinated induction of autophagy and suppression of the cGAS-STING pathway. We established an HK-2 cell injury model through cisplatin exposure. Following Hes intervention, cell viability was quantified via CCK-8 assays, apoptosis assessed by Annexin V-FITC/PI staining, and mitochondrial function evaluated through ATP production measurement, mitochondrial reactive oxygen species (ROS) detection and mitochondrial membrane potential analysis employing JC-1 staining. For in vivo validation, C57BL/6 mice developed AKI following single intraperitoneal cisplatin administration. Renal function parameters were determined through serum biochemistry, while renal histopathology was examined using periodic acid-Schiff (PAS) staining. Protein expression changes in mitochondrial autophagy markers and cGAS-STING pathway components were subsequently analyzed through immunofluorescence and Western blotting techniques. Autophagy modulators were employed to elucidate the precise mechanisms through which autophagy mediates Hes’s protective effects against cisplatin-induced AKI. In vitro, Hes intervention effectively reversed cisplatin-induced HK-2 cell injury and mitochondrial dysfunction while enhancing mitochondrial autophagy. Notably, the autophagy activator rapamycin alone, or co-administered with Hes produced comparable cytoprotective effects to Hes. Conversely, the autophagy inhibitor 3-methyladenine exacerbated cellular damage and partially attenuated Hes-mediated protection. In vivo studies confirmed Hes significantly ameliorated AKI through improved renal function and histopathology, concurrently reducing mitochondrial ROS levels while promoting autophagic clearance. Furthermore, Hes treatment potently suppressed activation of the cGAS-STING pathway in both experimental models. Hes ameliorates mitochondrial dysfunction in AKI by enhancing mitochondrial autophagy and inhibiting the cGAS-STING pathway.

橙皮素通过介导自噬和抑制cGAS-STING通路改善急性肾损伤的线粒体功能障碍
顺铂诱导的急性肾损伤(AKI)是抗癌治疗的严重并发症,没有有效的临床干预,经常需要减少化疗剂量或停药。天然产物由于其多靶点机制、多效性和低耐药潜力而成为抗顺铂肾毒性的有希望的治疗候选者。本研究探讨了橙皮素(Hes)通过协调诱导自噬和抑制cGAS-STING通路改善AKI期间线粒体功能障碍的治疗潜力。我们通过顺铂暴露建立HK-2细胞损伤模型。he干预后,通过CCK-8测定细胞活力,Annexin V-FITC/PI染色评估细胞凋亡,通过ATP生成测定、线粒体活性氧(ROS)检测和JC-1染色分析线粒体膜电位评估线粒体功能。为了在体内验证,C57BL/6小鼠在单次腹腔注射顺铂后发生AKI。血清生化法测定肾脏功能参数,周期性酸-希夫(PAS)染色法检测肾脏组织病理学。随后通过免疫荧光和Western blotting技术分析线粒体自噬标志物和cGAS-STING通路组分的蛋白表达变化。自噬调节剂被用来阐明自噬介导Hes对顺铂诱导的AKI的保护作用的确切机制。体外,he干预有效逆转顺铂诱导的HK-2细胞损伤和线粒体功能障碍,同时增强线粒体自噬。值得注意的是,自噬激活剂雷帕霉素单独或与Hes联合使用产生的细胞保护作用与Hes相当。相反,自噬抑制剂3-甲基腺嘌呤加重了细胞损伤,部分减弱了hes介导的保护作用。体内研究证实,he通过改善肾功能和组织病理学显著改善AKI,同时降低线粒体ROS水平,促进自噬清除。此外,在两种实验模型中,Hes处理都能有效抑制cGAS-STING通路的激活。他通过增强线粒体自噬和抑制cGAS-STING通路改善AKI的线粒体功能障碍。
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来源期刊
Journal of Molecular Histology
Journal of Molecular Histology 生物-细胞生物学
CiteScore
5.90
自引率
0.00%
发文量
68
审稿时长
1 months
期刊介绍: The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes. Major research themes of particular interest include: - Cell-Cell and Cell-Matrix Interactions; - Connective Tissues; - Development and Disease; - Neuroscience. Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance. The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.
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