Shikonin Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis to Attenuate Renal Ischemia/Reperfusion Injury by Activating the Sirt1/Nrf2/HO-1 Pathway.

IF 2.3 4区医学 Q2 PERIPHERAL VASCULAR DISEASE Kidney & blood pressure research Pub Date : 2025-01-01 Epub Date: 2024-12-11 DOI:10.1159/000542417

Qian Huang, Zilu Shi, Dandan Zheng, Huiqin Chen, Qiuhong Huang

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Abstract

Introduction: Shikonin is the major bioactive compound abundant in Lithospermum erythrorhizon and possesses diverse pharmacological properties. This study aimed to examine shikonin roles in experimental renal ischemia/reperfusion (I/R) injury.

Methods: Renal tissues and blood were collected from experimental renal I/R injury models. Kidney functions, structural injuries, and cellular death were assessed. Markers of endoplasmic reticulum (ER) stress were evaluated by RT-qPCR and Western blotting. The effect of shikonin on Sirt1/Nrf2/HO-1 signaling was detected by Western blotting and immunofluorescence staining. HK-2 cells that underwent hypoxia/reoxygenation (H/R) process were used to perform CCK-8 and flow cytometry.

Results: For in vivo analysis, renal dysfunctions and tissue structural damage induced by I/R were relieved by shikonin. Additionally, shikonin alleviated ER stress-induced apoptosis in I/R mice. For in vitro analysis, shikonin inhibited ER stress-stimulated apoptosis of H/R cells. Mechanistically, shikonin activated Sirt1/Nrf2/HO-1 signaling post-I/R, and inhibition of Sirt1 limited shikonin-mediated protection against ER stress-stimulated apoptosis in both animal and cellular models.

Conclusion: By activating Sirt1/Nrf2/HO-1 signaling, shikonin inhibits apoptosis caused by ER stress and relieves renal I/R injury.

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紫草素通过激活SIRT1/Nrf2/HO-1通路，抑制内质网应激诱导的细胞凋亡，减轻肾缺血再灌注损伤。

急性肾损伤具有高发病率和死亡率的特点，肾缺血/再灌注（I/R）损伤是一个关键的诱导剂。紫草素是从紫草根中提取的主要生物活性化合物，具有多种药理作用。本研究旨在探讨紫草素在肾I/R损伤中的生物学功能。方法：建立肾I/R损伤实验模型，检测紫草素在肾I/R损伤中的作用。采集小鼠肾组织和血液。血清肌酐和尿素氮水平用商用试剂盒评估。肾损伤检测采用KIM-1蛋白水平测定、苏木精染色、伊红染色和周期性酸-希夫染色。通过细胞凋亡相关蛋白的表达及TUNEL染色评价肾组织的凋亡情况。内质网应激通过测量内质网应激特异性标记物来测定。western blotting和免疫荧光染色分析了紫草素作用的可能机制。CCK-8和流式细胞术检测细胞活力和凋亡。结果：在体内实验中，紫草素可减轻I/R所致的肾功能障碍和组织结构损伤。此外，紫草素可减轻I/R小鼠肾组织内质网应激介导的细胞凋亡。此外，在I/R后，紫草素激活了SIRT1/Nrf2/HO-1通路，抑制SIRT1限制了紫草素介导的对内质网应激刺激的细胞凋亡的保护作用。在H/R条件下，紫草素对内质网应激诱导的细胞凋亡有抑制作用。此外，SIRT1的抑制也减弱了紫草素介导的对内质网应激诱导的细胞凋亡的保护作用。结论：紫草素可通过激活SIRT1/Nrf2/HO-1通路，抑制内质网应激引起的肾I/R损伤的凋亡，从而减轻肾I/R损伤。

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来源期刊

Kidney & blood pressure research 医学-泌尿学与肾脏学

CiteScore

4.80

自引率

3.60%

发文量

审稿时长

6-12 weeks

期刊介绍： This journal comprises both clinical and basic studies at the interface of nephrology, hypertension and cardiovascular research. The topics to be covered include the structural organization and biochemistry of the normal and diseased kidney, the molecular biology of transporters, the physiology and pathophysiology of glomerular filtration and tubular transport, endothelial and vascular smooth muscle cell function and blood pressure control, as well as water, electrolyte and mineral metabolism. Also discussed are the (patho)physiology and (patho) biochemistry of renal hormones, the molecular biology, genetics and clinical course of renal disease and hypertension, the renal elimination, action and clinical use of drugs, as well as dialysis and transplantation. Featuring peer-reviewed original papers, editorials translating basic science into patient-oriented research and disease, in depth reviews, and regular special topic sections, ''Kidney & Blood Pressure Research'' is an important source of information for researchers in nephrology and cardiovascular medicine.