TRPA1 通过调节内质网应激-线粒体损伤促进顺铂诱导的急性肾损伤。
TRPA1 promotes cisplatin-induced acute kidney injury via regulating the endoplasmic reticulum stress-mitochondrial damage.
机构信息
Department of Nephrology, West China Hospital, Sichuan University, 37 Guoxue Alley, Wuhou District, Chengdu, 610044, China.
Department of Nephrology, Sichuan Provincial People's Hospital Jinniu Hospital, Chengdu Jinniu District People's Hospital, Chengdu, China.
出版信息
J Transl Med. 2023 Oct 5;21(1):695. doi: 10.1186/s12967-023-04351-9.
BACKGROUND
Cisplatin is a widely used and effective chemotherapeutic agent against cancer. However, nephrotoxicity is one of the most common side effects of cisplatin, and it can proceed to acute kidney injury (AKI). Studies have reported that activation of transient receptor potential ankyrin-1 (TRPA1) mediates cisplatin-induced renal tubular cytotoxic injury. The aim of this study was to investigate the mechanism of TRPA1 in promoting cisplatin-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage.
METHODS
A cisplatin-induced HK-2 cell model in vitro and mouse model in vivo were established. The mechanism of TRPA1 promotes AKI was elucidated by H&E staining, TUNEL staining, transmission electron microscope (TEM), immunofluorescence, CCK-8 viability assays, flow cytometry, Western blotting, JC-1 assay, and enzyme linked immunosorbent assay (ELISA).
RESULT
In vivo and in vitro, HC-030031 reduced cisplatin-induced Scr and BUN level elevations; improved cisplatin-induced renal tissue injury, apoptosis, and mitochondrial dysfunction; elevated the reduced ERS-associated proteins glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), and C/EBP homologous protein (CHOP) levels induced by cisplatin; reduced the elevated optic atrophy 1 (OPA1), mito-fusion 1 (MFN1), and mito-fusion 2 (MFN2) protein levels, and elevated phospho-dynamin-related protein 1 (p-DRP1) and mitochondrial fission factor (MFF) protein levels. HC-030031 also reduced the mitochondria-associated endoplasmic reticulum membrane (MAM) structure. In addition, TRPA1 agonists also decreased cell proliferation, increased apoptosis, and triggered mitochondrial dysfunction and calcium overload in HK-2 cells via modulation of MAM. ERS inhibitors and GRP75 inhibitors reversed these changes caused by TRPA1 agonists.
CONCLUSION
Our findings suggest that TRPA1 enhances cisplatin-induced AKI via modulation of ERS and mitochondrial damage.
背景
顺铂是一种广泛应用于癌症治疗的有效化疗药物。然而，顺铂的肾毒性是其最常见的副作用之一，可导致急性肾损伤（AKI）。研究表明，瞬时受体电位锚蛋白-1（TRPA1）的激活介导了顺铂诱导的肾小管细胞毒性损伤。本研究旨在探讨 TRPA1 通过调节内质网应激（ERS）-线粒体损伤促进顺铂诱导的 AKI 的机制。
方法
建立了体外 HK-2 细胞模型和体内小鼠模型。通过 H&E 染色、TUNEL 染色、透射电镜（TEM）、免疫荧光、CCK-8 细胞活力检测、流式细胞术、Western blot、JC-1 检测和酶联免疫吸附试验（ELISA）等方法阐明了 TRPA1 促进 AKI 的机制。
结果
在体内和体外，HC-030031 降低了顺铂诱导的 Scr 和 BUN 水平升高；改善了顺铂诱导的肾组织损伤、凋亡和线粒体功能障碍；上调了顺铂诱导的 ERS 相关蛋白葡萄糖调节蛋白 78（GRP78）、葡萄糖调节蛋白 75（GRP75）和 C/EBP 同源蛋白（CHOP）水平；降低了顺铂诱导的视神经萎缩蛋白 1（OPA1）、线粒体融合蛋白 1（MFN1）和线粒体融合蛋白 2（MFN2）蛋白水平，上调了磷酸化动力相关蛋白 1（p-DRP1）和线粒体分裂因子（MFF）蛋白水平。HC-030031 还降低了线粒体相关内质网膜（MAM）结构。此外，TRPA1 激动剂还通过调节 MAM 降低了 HK-2 细胞的增殖、增加了凋亡，并引发了线粒体功能障碍和钙超载。ERS 抑制剂和 GRP75 抑制剂逆转了 TRPA1 激动剂引起的这些变化。
结论
我们的研究结果表明，TRPA1 通过调节 ERS 和线粒体损伤增强了顺铂诱导的 AKI。
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