沉浸式翻译中药的双面刃：系统综述其肾毒性与肾保护机制
The double-edged sword of traditional Chinese medicine: a systematic review of its nephrotoxicity and nephroprotective mechanisms
摘要
Summary
近年来，中药在肾脏药理学和毒理学领域取得了显著进展。本文通过系统整理近十年的相关文献，全面总结并比较了中药的肾毒性及其肾保护机制。尽管已有许多关于中药肾毒性的综述，但有关其肾保护作用的研究相对较少。因此，本文重点分析了马兜铃酸、雷公藤和大黄等中药成分的肾毒性及其解毒机制，超剂量或长期使用引起的肾毒性机制，以及中药在改善顺铂、环孢霉素A及其他药物诱导的肾毒性方面的作用机制。研究表明，部分中药在正常剂量和病理条件下具有显著的肾保护作用，但在超剂量或长期使用情况下则表现出肾毒性。通过对这些机制的深入比较和分析，本综述旨在全面总结中药的肾毒性和肾保护作用，帮助医务人员和研究者更加全面、客观地理解和应用中药，最大限度地发挥其治疗潜力，同时降低其潜在毒性风险。
In recent years, traditional Chinese medicine has made significant progress in the fields of renal pharmacology and toxicology. This article comprehensively summarizes and compares the nephrotoxicity of traditional Chinese medicine and its nephroprotective mechanisms by systematically sorting out relevant literature in the past ten years. Although there have been many reviews on the nephrotoxicity of traditional Chinese medicines, there are relatively few studies on their nephroprotective effects. Therefore, this article focuses on the analysis of the nephrotoxicity and detoxification mechanism of traditional Chinese medicine ingredients such as aristolochic acid, tripterygium wilfordii, and rhubarb, the nephrotoxicity mechanism caused by excessive dosage or long-term use, and the role of traditional Chinese medicine in improving cisplatin, cyclosporine A, and other Mechanisms of action in drug-induced nephrotoxicity. Studies have shown that some traditional Chinese medicines have significant nephroprotective effects under normal doses and pathological conditions, but exhibit nephrotoxicity when excessive doses or long-term use occur. Through in-depth comparison and analysis of these mechanisms, this review aims to comprehensively summarize the nephrotoxicity and nephroprotective effects of traditional Chinese medicines, help medical staff and researchers understand and apply traditional Chinese medicines more comprehensively and objectively, and maximize their therapeutic potential while also Reduce its potential toxicity risk.
一、引言
I. Introduction
作为中国传统医学的重要组成部分，中药拥有数千年的应用历史，其疗效和多样性在全球范围内备受关注。然而，随着现代药理学和毒理学研究的深入，中药的安全性问题逐渐显现，尤其是一些中药成分的肾毒性，引发了广泛的讨论和担忧。
As an important part of traditional Chinese medicine, traditional Chinese medicine has a history of application for thousands of years, and its efficacy and diversity have attracted worldwide attention. However, with the deepening of modern pharmacology and toxicology research, the safety issues of traditional Chinese medicine have gradually emerged, especially the nephrotoxicity of some traditional Chinese medicine ingredients, which has triggered extensive discussions and concerns.
中药的肾毒性已成为影响其临床应用的重要因素。根据《中国药品不良反应信息通报》的数据，截至2019年5月1日，共收录了52种存在不良反应的中药药品，其中32种存在肾毒性风险，占所有不良反应的61.5%。这些数据表明，肾毒性是中药临床应用中必须重视的一个关键问题。
The nephrotoxicity of traditional Chinese medicine has become an important factor affecting its clinical application. According to the "China Adverse Drug Reaction Information Bulletin", as of May 1, 2019, a total of 52 kinds of traditional Chinese medicine drugs with adverse reactions have been included, 32 of which have the risk of nephrotoxicity, accounting for 61.5% of all adverse reactions. These data indicate that nephrotoxicity is a key issue that must be paid attention to in the clinical application of traditional Chinese medicine.
然而，中药不仅具有肾毒性，在某些病理状态下也显示出显著的肾保护作用。例如，砒霜（即三氧化二砷，ATO）在历史上常被用作毒药，但在现代医学中，特别是在治疗急性早幼粒细胞白血病（APL）方面，具有重要的治疗作用。ATO通过靶向降解PML-RARA融合蛋白并促进白血病细胞分化和凋亡，显著提高了APL患者的生存率[1][2]。这表明，砒霜在正常生理状态下服用是有毒的，但在特定病理状态下具有治疗作用。同样，雷公藤在大鼠病理状态下可通过色氨酸代谢途径发挥肾保护作用，而在正常状态下则通过烟酸和烟酰胺代谢途径表现出肾毒性[3]。这些例子表明，部分中药在不同条件下可以表现出相反的作用。
However, traditional Chinese medicine not only has nephrotoxicity, but also shows significant nephroprotective effects in certain pathological conditions. For example, arsenic (i.e., arsenic trioxide, ATO) was often used as a poison in history, but it has an important therapeutic role in modern medicine, especially in the treatment of acute promyelocytic leukemia (APL). ATO significantly improves the survival rate of APL patients by targeting the degradation of PML-RARA fusion protein and promoting leukemia cell differentiation and apoptosis [1] [2] . This shows that arsenic is toxic when taken under normal physiological conditions, but has therapeutic effects under specific pathological conditions. Similarly, Tripterygium wilfordii can exert a nephroprotective effect through the tryptophan metabolism pathway in rats under pathological conditions, while under normal conditions it exhibits nephrotoxicity through the niacin and nicotinamide metabolism pathways [3] . These examples show that some traditional Chinese medicines can exhibit opposite effects under different conditions.
本综述旨在系统分析和比较中药的肾毒性及其肾保护作用，以更全面和客观的视角看待中药的使用。通过探讨马兜铃酸、雷公藤和大黄等主要中药成分的肾毒性和解毒机制，以及中药在改善药物诱导肾毒性中的潜在价值，我们希望为中药的安全性评价和临床应用提供科学依据，推动其在现代医学中的合理应用。
This review aims to systematically analyze and compare the nephrotoxicity and nephroprotective effects of traditional Chinese medicines, and view the use of traditional Chinese medicines from a more comprehensive and objective perspective. By exploring the nephrotoxicity and detoxification mechanisms of major traditional Chinese medicine ingredients such as aristolochic acid, tripterygium wilfordii, and rhubarb, as well as the potential value of traditional Chinese medicine in improving drug-induced nephrotoxicity, we hope to provide scientific basis for the safety evaluation and clinical application of traditional Chinese medicine and promote Its rational application in modern medicine.
二、马兜铃酸的肾毒性机制和解毒机制
2. Nephrotoxicity and detoxification mechanisms of aristolochic acid
马兜铃酸（Aristolochic Acids，AAs）是一类硝基菲甲酸类化合物，广泛存在于马兜铃属和细辛属植物中[4]。常见含马兜铃酸的中药包括关木通、广防己、马兜铃、细辛、青木香和天仙藤[5]。这些中草药的肾毒性和致癌性主要与其含有的AA成分密切相关。众所周知，马兜铃酸具有高度致癌性。2012年，国际癌症研究机构（IARC）将这些化合物列为I类致癌物[6]。研究表明，马兜铃酸及其相关中药可引起严重的肾毒性，甚至导致肾功能衰竭[7]。据报道，AA-I具有显著的肾毒性、遗传毒性和潜在的致癌性[8][9]。相比之下，AA-II虽可引起轻度肾损伤和遗传毒性，但其毒性作用明显弱于AA-I[10]。因此，AA-I可能是诱发毒性的关键危险因素[11]。
Aristolochic Acids (AAs) are a type of nitrophenanthrene acid compounds that are widely present in plants of the genus Aristolochia and Asarum [4] . Common Chinese medicines containing aristolochic acid include Akebia acuta, Fangchi fangchi, Aristolochia acuta, Asarum, Aristolochia and Helix wilfordii [5] . The nephrotoxicity and carcinogenicity of these Chinese herbal medicines are mainly closely related to the AA components they contain. Aristolochic acid is known to be highly carcinogenic. In 2012, the International Agency for Research on Cancer (IARC) classified these compounds as Class I carcinogens [6] . Studies have shown that aristolochic acid and its related traditional Chinese medicines can cause severe nephrotoxicity and even lead to renal failure [7] . It has been reported that AA-I has significant nephrotoxicity, genotoxicity and potential carcinogenicity [8] [9] . In contrast, although AA-II can cause mild renal damage and genotoxicity, its toxic effects are significantly weaker than AA-I [10] . Therefore, AA-I may be a key risk factor for inducing toxicity [11] .
1.AAI的肾毒性机制
1. Mechanism of nephrotoxicity of AAI
1.1．常见的AAI 肾毒性机制
1.1. Common mechanisms of AAI nephrotoxicity
1.1.1内质网应激
1.1.1 Endoplasmic reticulum stress
内质网应激是AAI肾毒性机制之一。AAI诱导内质网应激，激活CHOP[12]和Caspase-12[13][14]等细胞凋亡信号通路，启动肾小管上皮细胞的凋亡程序。
Endoplasmic reticulum stress is one of the mechanisms of AAI nephrotoxicity. AAI induces endoplasmic reticulum stress and activates CHOP [12] and Caspase-12 [13] < b5> and other apoptosis signaling pathways initiate the apoptosis program of renal tubular epithelial cells.
1.1.2氧化应激
1.1.2 Oxidative stress
氧化应激是AAI肾毒性机制之一。AAI可增加大鼠肾组织中丙二醛(MDA)含量，降低超氧化物歧化酶(SOD)活性[15]。AAI孵育肾小管上皮细胞可产生大量活性氧簇和氮类(ROS/RNS)[16]，并通过激活DNA损伤通路诱导细胞周期阻滞。
Oxidative stress is one of the mechanisms of AAI nephrotoxicity. AAI can increase the content of malondialdehyde (MDA) and reduce the activity of superoxide dismutase (SOD) in rat kidney tissue [15] . Incubating renal tubular epithelial cells with AAI can produce a large amount of reactive oxygen species and nitrogen species (ROS/RNS) [16] and induce cells by activating DNA damage pathways Cycle block.
1.1.3线粒体损伤
1.1.3 Mitochondrial damage
线粒体损伤是AAI肾毒性机制之一。AAI抑制ADP/ATP转运酶活性，显著降低肾小管上皮细胞的线粒体膜电位和ATP含量[17]，AAI通过增加线粒体通透性转换孔（PTP）开放时间，导致细胞色素C释放，激活Caspase-9和Caspase-3[18]最终导致细胞凋亡。
Mitochondrial damage is one of the mechanisms of AAI nephrotoxicity. AAI inhibits the activity of ADP/ATP transferase and significantly reduces the mitochondrial membrane potential and ATP content of renal tubular epithelial cells [17] . AAI increases the opening of mitochondrial permeability transition pore (PTP). time, leading to the release of cytochrome c, activating Caspase-9 and Caspase-3 [18] and ultimately leading to cell apoptosis.
1.1.4miRNA调控
miRNA是AAI肾毒性机制之一。Pu等发现，在AAI诱导的大鼠急性肾损伤中，21个miRNA在第2、4、6天显著上调，其中miR-21-3p在第4、6天显著上调，并且在血浆中早于肌酐和尿素氮升高，因此miR-21-3p可作为AAⅠ诱导大鼠急性肾损伤的新的标志物[19]。Jenkins等的研究表明，AAI诱导的细胞周期阻滞由miRNA调控，miR-192在G2/M阻滞中发挥关键作用[20]。
miRNA is one of the mechanisms of AAI nephrotoxicity. Pu et al. found that in AAI-induced acute kidney injury in rats, 21 miRNAs were significantly up-regulated on days 2, 4, and 6, among which miR-21-3p was significantly up-regulated on days 4 and 6, and appeared in plasma earlier than Creatinine and urea nitrogen are increased, so miR-21-3p can be used as a new marker of AAⅠ-induced acute kidney injury in rats [19] . Studies by Jenkins et al. have shown that AAI-induced cell cycle arrest is regulated by miRNA, and miR-192 plays a key role in G2/M arrest [20] .
1.1.5DNA损伤
1.1.5DNA damage
DNA损伤是AAI肾毒性机制之一。AAs在体内与嘌呤共价结合形成 AAs-DNA加合物，导致 A-T 与 T-A 碱基突变，影响细胞代谢过程，此被认为是 AAs 诱导肾毒性的关键因素[21]。
DNA damage is one of the mechanisms of AAI nephrotoxicity. AAs covalently combine with purine in the body to form AAs-DNA adducts, leading to A-T and T-A base mutations, affecting cellular metabolic processes. This is considered a key factor in AAs-induced nephrotoxicity [21] .
1.2.ALI诱导肾毒性的机制及其预防靶点
1.2. The mechanism of ALI-induced nephrotoxicity and its preventive targets
马兜铃酸代谢产物Aristolactam I (ALI)在其肾毒性机制中发挥了关键作用。ALI可导致人近端肾小管上皮细胞发生铁死亡反应。与细胞凋亡、坏死和自噬相比，铁死亡在ALI诱导的肾小管上皮细胞死亡中起着主导作用。线粒体铁超载介导的抗氧化系统抑制是ALI诱导肾小管上皮细胞铁死亡的主要毒性机制。
Aristolochic acid metabolite Aristolactam I (ALI) plays a key role in its nephrotoxicity mechanism. ALI can induce ferroptosis in human proximal renal tubular epithelial cells. Compared with apoptosis, necrosis, and autophagy, ferroptosis plays a dominant role in ALI-induced renal tubular epithelial cell death. Inhibition of the antioxidant system mediated by mitochondrial iron overload is the main toxic mechanism of ALI-induced ferroptosis in renal tubular epithelial cells.
Nrf2-HO-1/GPX4抗氧化系统能够减轻ALI诱导的氧化应激和铁死亡，从而减少肾毒性。因此，Nrf2-HO-1/GPX4抗氧化系统可能是预防ALI诱导的肾病的重要靶点[22]。
The Nrf2-HO-1/GPX4 antioxidant system can alleviate ALI-induced oxidative stress and ferroptosis, thereby reducing nephrotoxicity. Therefore, the Nrf2-HO-1/GPX4 antioxidant system may be an important target for preventing ALI-induced nephropathy [22] .
1.3.Oat1和Oat3在AAI诱导肾毒性中的关键角色及协同作用
1.3. The key role and synergistic effect of Oat1 and Oat3 in AAI-induced nephrotoxicity
有机阴离子转运体1（Oat1）和有机阴离子转运体3（Oat3）在马兜铃酸（AAI）诱导的肾毒性中起关键作用。AAI是马兜铃酸肾病（AAN）的主要致病因素，AAN的特征是严重的肾纤维化和上尿路癌。由于有机阴离子运输的改变，尿液代谢谱发生变化，进一步损伤近端小管。AAI通过乳腺癌耐药蛋白（BCRP）排出，而非通过P-糖蛋白（P-gp）或多药耐药相关蛋白2（MRP2）[23]。此外，表达Oat1和细胞色素P450酶1A2（CYP1A2）的细胞在AAI暴露下的活力显著下降，这表明Oat1和CYP1A2可能在AAI引起的毒性中发挥协同作用[24]。
Organic anion transporter 1 (Oat1) and organic anion transporter 3 (Oat3) play key roles in aristolochic acid (AAI)-induced nephrotoxicity. AAI is a major causative factor in aristolochic acid nephropathy (AAN), which is characterized by severe renal fibrosis and upper urinary tract cancer. Due to altered transport of organic anions, the metabolic profile of urine changes, further damaging the proximal tubules. AAI is excreted through breast cancer resistance protein (BCRP), not through P-glycoprotein (P-gp) or multidrug resistance-related protein 2 (MRP2) [23] . Furthermore, the viability of cells expressing Oat1 and cytochrome P450 enzyme 1A2 (CYP1A2) was significantly reduced under AAI exposure, suggesting that Oat1 and CYP1A2 may play a synergistic role in AAI-induced toxicity [24]
1.4.马兜铃酸通过靶向线粒体蛋白诱导肾毒性的机制
1.4. The mechanism of aristolochic acid inducing nephrotoxicity by targeting mitochondrial proteins
通过细胞热稳定性分析（CETSA）实验验证，马兜铃酸（AAs）可以直接结合IDH2、MDH2、PKM、PC、LDHA和HK2蛋白。酶活性测定表明，AAs抑制了这些酶的功能和表达。AAs可诱导线粒体去极化并抑制ATP的产生，从而导致细胞凋亡[25]。综上所述，AAs通过靶向线粒体蛋白并破坏其平衡来诱导线粒体凋亡。此外，由于AAs可通过有机阴离子转运体（OATs）选择性重吸收，因此AAs会优先靶向肾脏中的肾小管上皮细胞（PTECs）[26]。
It was verified by Cell Thermal Stability Analysis (CETSA) experiments that aristolochic acid (AAs) can directly bind to IDH2, MDH2, PKM, PC, LDHA and HK2 proteins. Enzyme activity assays showed that AAs inhibited the function and expression of these enzymes. AAs can induce mitochondrial depolarization and inhibit ATP production, leading to cell apoptosis [25] . In summary, AAs induce mitochondrial apoptosis by targeting mitochondrial proteins and disrupting their balance. In addition, because AAs can be selectively reabsorbed through organic anion transporters (OATs), AAs preferentially target renal tubular epithelial cells (PTECs) in the kidney [26] .
基于活性的蛋白质分析（ABPP）结合生物正交点击化学反应和CETSA，以及代谢组学研究，首次揭示了AAI直接靶向脂质代谢、氨基酸代谢、有氧呼吸和TCA循环等代谢过程中的多个关键酶，从而损害线粒体功能并诱导肾脏细胞凋亡[27]。
Activity-based protein profiling (ABPP) combined with bioorthogonal click chemistry reactions and CETSA, as well as metabolomic studies, revealed for the first time that AAI directly targets multiple metabolic processes such as lipid metabolism, amino acid metabolism, aerobic respiration, and TCA cycle. A key enzyme, thereby damaging mitochondrial function and inducing renal cell apoptosis [27] .
2. AAI肾毒性的解毒机制
2. Detoxification mechanism of AAI nephrotoxicity
CYP1A1和CYP1A2是参与AAI解毒的重要酶[28][29]。
CYP1A1 and CYP1A2 are important enzymes involved in AAI detoxification [28] [29] .
黄芩苷显著改善了AAI诱导的肾毒性。它通过诱导肝脏中CYP1A1/2的表达，降低了AAI处理后小鼠的血尿素氮和肌酐水平，减轻了AAI引起的肾损伤。这种保护作用可能是通过在肝脏中诱导ahr依赖性CYP1A1/2的表达，从而显著降低AAI的浓度实现的[30]。
Baicalin significantly improved AAI-induced nephrotoxicity. It reduces blood urea nitrogen and creatinine levels in mice treated with AAI and alleviates AAI-induced renal damage by inducing the expression of CYP1A1/2 in the liver. This protective effect may be achieved by inducing ahr-dependent CYP1A1/2 expression in the liver, thereby significantly reducing the concentration of AAI [30] .
丹参酮I同样显著改善了AAI诱导的肾毒性。它通过诱导CYP1A1和CYP1A2的表达，显著促进了AAI的代谢，从而有效减少了AAI引起的肾损伤。此外，荧光素酶实验结果显示，丹参酮I显著增强了CYP1A1和CYP1A2的转录活性。Thomas等人的研究表明，CYP1A2在AAI解毒过程中比CYP1A1更为有效[31]。
Tanshinone I also significantly improved AAI-induced nephrotoxicity. It significantly promotes the metabolism of AAI by inducing the expression of CYP1A1 and CYP1A2, thereby effectively reducing renal damage caused by AAI. In addition, luciferase assay results showed that tanshinone I significantly enhanced the transcriptional activities of CYP1A1 and CYP1A2. Research by Thomas et al. shows that CYP1A2 is more effective than CYP1A1 in the detoxification process of AAI [31] .
三、雷公藤的肾毒性机制和解毒机制
3. Nephrotoxicity and detoxification mechanisms of Tripterygium wilfordii
1.雷公藤的肾毒性机制
1The nephrotoxicity mechanism of Tripterygium wilfordii
雷公藤（Tripterygium wilfordii Hook. F., TwHF）是一种有效治疗类风湿性关节炎（RA）的中药，广泛用于抗炎和免疫抑制治疗[32]。然而，雷公藤的使用伴随着较高的不良反应发生率，约为26.7%至58.1%[33],其中肾毒性占5.81%。在使用雷公藤制剂治疗20天后，观察到患者血尿氮（BUN）和血清肌酐（Scr）水平升高，以及少尿的症状[34]。肾活检标本显示肾小管上皮细胞坏死和间质炎症细胞浸润[35]，提示近端肾小管是其敏感靶点之一。
Tripterygium wilfordii Hook. F., TwHF) is an effective traditional Chinese medicine for the treatment of rheumatoid arthritis (RA) and is widely used in anti-inflammatory and immunosuppressive treatments [32] . However, the use of Tripterygium wilfordii is accompanied by a high incidence of adverse reactions, ranging from 26.7% to 58.1% [33] , of which nephrotoxicity accounts for 5.81%. After 20 days of treatment with Tripterygium wilfordii preparations, the patient was observed to have elevated levels of blood urinary nitrogen (BUN) and serum creatinine (Scr), as well as symptoms of oliguria [34] . Renal biopsy specimens showed necrosis of renal tubular epithelial cells and infiltration of interstitial inflammatory cells [35] , suggesting that the proximal renal tubule is one of its sensitive targets.
1.1.Oat1和Oat3在雷公藤甲素诱导肾毒性中的关键作用
1.1. The key role of Oat1 and Oat3 in triptolide-induced nephrotoxicity
有机阴离子转运体1（Oat1）和有机阴离子转运体3（Oat3）在雷公藤（TG）诱导的肾毒性中发挥关键作用。TG显著降低肾脏中Oat1和Oat3的mRNA表达，并减少肾皮质切片中对-氨基马尿酸（PAH）的积累[36]。雷公藤甲素（TP）被认为是TG的主要肾毒性成分，其毒性作用靶向近端小管，导致细胞连接破坏和小管旁通透性改变[37][38]。在TP暴露下，肾损伤表现为代谢物的逐步改变，从乙酸到丙酮的增加，显示损伤从肾皮质向肾乳头转移[39]。由于Oat1主要在近端小管S2段表达，而Oat3在S1、S2和S3段均有表达，Oat1和Oat3的抑制可能与近端小管损伤密切相关[14]。此外，TP是P-gp的底物，但不影响MRP2或其他转运蛋白，表明OATs功能的抑制可能导致肾脏内源性物质如尿毒症毒素的失衡，从而加剧肾损伤[40][41]。
Organic anion transporter 1 (Oat1) and organic anion transporter 3 (Oat3) play key roles in tripterygium wilfordii (TG)-induced nephrotoxicity. TG significantly reduced the mRNA expression of Oat1 and Oat3 in the kidney and reduced the accumulation of p-aminohippuric acid (PAH) in renal cortical slices [36] . Triptolide (TP) is considered to be the main nephrotoxic component of TG. Its toxic effects target the proximal tubules, leading to the destruction of cell connections and changes in paratubular permeability [37] [38] . Under TP exposure, renal injury manifests as a stepwise change in metabolites, from an increase in acetic acid to acetone, indicating a shift of damage from the renal cortex to the renal papilla [39] . Since Oat1 is mainly expressed in the S2 segment of the proximal tubule, while Oat3 is expressed in the S1, S2, and S3 segments, the inhibition of Oat1 and Oat3 may be closely related to proximal tubule injury [14]. In addition, TP is a substrate of P-gp but does not affect MRP2 or other transporters, indicating that inhibition of OATs function may lead to an imbalance of endogenous substances in the kidney such as uremic toxins, thereby exacerbating kidney damage [40] [41] .
1.2.雷公藤甲素的肾毒性机制
1.2. Mechanism of nephrotoxicity of triptolide
1.2.1.雷公藤甲素诱导肾毒性中的cGAS-STING信号通路激活机制
1.2.1. Activation mechanism of cGAS-STING signaling pathway in triptolide-induced nephrotoxicity
雷公藤甲素（TPL）是从雷公藤中提取的一种具有抗肿瘤等多种药理活性的生物活性成分。然而，其肾毒性限制了临床应用。TPL在体内和体外均能激活肾小管细胞的cGAS-STING信号通路，增加STING、TBK1和IRF3的磷酸化水平，并上调cGAS-STING信号通路中IFNβ的表达。此外，因BACH1表达增加，抗氧化酶HMOX1的转录表达降低，氧化应激诱导的mtDNA损伤和DNA泄漏进一步激活cGAS-STING信号通路。综上所述，cGAS-STING信号通路在TPL诱导的肾毒性中起重要作用[42]。
Triptolide (TPL) is a bioactive ingredient extracted from Tripterygium wilfordii with various pharmacological activities such as anti-tumor. However, its nephrotoxicity limits clinical application. TPL can activate the cGAS-STING signaling pathway in renal tubular cells both in vivo and in vitro, increase the phosphorylation levels of STING, TBK1, and IRF3, and upregulate the expression of IFNβ in the cGAS-STING signaling pathway. In addition, due to increased BACH1 expression and decreased transcriptional expression of the antioxidant enzyme HMOX1, oxidative stress-induced mtDNA damage and DNA leakage further activate the cGAS-STING signaling pathway. In summary, the cGAS-STING signaling pathway plays an important role in TPL-induced nephrotoxicity [42] .
1.2.2．OCT2在TNF-α介导的雷公藤甲素肾毒性中的关键作用
1.2.2. The key role of OCT2 in TNF-α-mediated triptolide nephrotoxicity
研究表明，在类风湿性关节炎状态下，TNF-α暴露可诱导有机阳离子转运蛋白2（OCT2）的表达，从而将更多的雷公藤甲素（TPL）转运至肾皮质，进一步加重肾损伤。因此，有机阳离子转运蛋白2在雷公藤甲素诱导的肾毒性中起着关键作用[43]。
Studies have shown that in rheumatoid arthritis, TNF-α exposure can induce the expression of organic cation transporter 2 (OCT2), thereby transporting more triptolide (TPL) to the renal cortex, further aggravating renal damage. . Therefore, organic cation transporter 2 plays a key role in triptolide-induced nephrotoxicity [43] .
1.2.3.网络药理学与RNA-seq揭示的雷公藤甲素肾毒性靶点
1.2.3. Triptolide nephrotoxicity targets revealed by network pharmacology and RNA-seq
通过网络药理学方法预测雷公藤甲素（TPL）毒性相关的候选靶点，并通过深度RNA-seq分析表征了三个转录元件的特征，包括蛋白质编码基因（PCGs）、长链非编码RNA（lncRNAs）和环状RNA（circRNAs），以及它们与TPL治疗大鼠肾毒性的关系。研究结果显示，c-Jun是TPL的潜在靶点，Per1相关的昼夜节律信号在TPL诱导的肾毒性中起重要作用[44]。
A network pharmacology approach was used to predict triptolide (TPL) toxicity-related candidate targets, and deep RNA-seq analysis was used to characterize the characteristics of three transcription elements, including protein-coding genes (PCGs), long non-coding RNAs ( lncRNAs) and circular RNAs (circRNAs), and their relationship with nephrotoxicity in TPL-treated rats. Research results show that c-Jun is a potential target of TPL, and Per1-related circadian signaling plays an important role in TPL-induced nephrotoxicity [44] .
2.雷公藤肾毒性的解毒机制
2. Detoxification mechanism of Tripterygium wilfordii nephrotoxicity
HK-2细胞研究表明，甘草酸糖苷（GA）和雷公藤苷（TG）可以通过抑制RhoA/ROCK1/p-MLC信号通路的激活来维持紧密连接的完整性，从而减轻TG诱导的肾小管损伤[45]。
HK-2 cell studies have shown that glycyrrhizinate (GA) and triptolide (TG) can maintain the integrity of tight junctions by inhibiting the activation of the RhoA/ROCK1/p-MLC signaling pathway, thereby alleviating TG-induced tubular injury. [45] .
大黄的肾保护机制和肾毒性机制
Renal protective and nephrotoxic mechanisms of rhubarb
大黄含有多种化合物，蒽醌类化合物是最重要的活性成分之一，主要包括大黄素、大黄酸、大黄酚、芦荟大黄素及其他物质。
Rhubarb contains a variety of compounds, and anthraquinones are one of the most important active ingredients, mainly including emodin, rhein, chrysophanol, aloe-emodin and other substances.
1.大黄及其主要活性成分的肾保护机制
1 Renal protective mechanism of rhubarb and its main active components
1.1.大黄蒽醌类化合物的抗氧化与抗炎机制
1.1. Antioxidant and anti-inflammatory mechanisms of rhubarb anthraquinones
大黄蒽醌类化合物能够减轻氧化应激和炎症反应对肾细胞的损害。其中，大黄酸通过激活sirtuin-3 (SIRT3)/FOXO3α信号通路发挥显著的抗氧化作用[46]。其抗炎活性体现在大黄素可抑制NRK-52E细胞中toll样受体-2(TLR2)和促炎因子（TNF-α、IL-1β、IL-6）的mRNA和蛋白表达上调[47]。
Rhubarb anthraquinones can reduce the damage to renal cells caused by oxidative stress and inflammatory reactions. Among them, rhein exerts a significant antioxidant effect by activating the sirtuin-3 (SIRT3)/FOXO3α signaling pathway [46] . Its anti-inflammatory activity is reflected in the fact that emodin can inhibit the upregulation of mRNA and protein expression of toll-like receptor-2 (TLR2) and pro-inflammatory factors (TNF-α, IL-1β, IL-6) in NRK-52E cells [47] .
1.2.大黄蒽醌类成分通过调节凋亡因子保护肾细胞
1.2 Rhubarb anthraquinones protect renal cells by regulating apoptosis factors
大黄蒽醌类成分可调节细胞凋亡相关因子的表达。如下调Bcl-2、caspase-3、cleaved caspase-3的表达，上调Bax的表达，从而抑制肾细胞的凋亡[48]。
The anthraquinone components of rhubarb can regulate the expression of apoptosis-related factors. By downregulating the expression of Bcl-2, caspase-3, and cleaved caspase-3, and upregulating the expression of Bax, thereby inhibiting the apoptosis of renal cells [48] .
1.3.大黄及其活性成分的抗肾纤维化机制
13. Anti-renal fibrosis mechanism of rhubarb and its active ingredients
大黄通过降低促纤维化因子的表达，抑制肌成纤维细胞的形成，减轻肾纤维化。大黄对肾小管纤维化和肾小球硬化有明显的抑制作用，其机制与阻止HK-2细胞上皮间充质转化密切相关[49]。
Rhubarb reduces the expression of profibrotic factors, inhibits the formation of myofibroblasts, and reduces renal fibrosis. Rhubarb has a significant inhibitory effect on renal tubular fibrosis and glomerulosclerosis, and its mechanism is closely related to preventing epithelial-mesenchymal transition of HK-2 cells [49] .
2.大黄及其主要活性成分的肾毒性机制
2 Nephrotoxicity mechanisms of rhubarb and its main active components
2.1.大黄素的肾毒性机制
2.1. Mechanism of nephrotoxicity of emodin
大黄素通过增强PPARγ表达和稳定性，激活线粒体途径，引发caspase 3依赖性凋亡，从而在人体肾近曲小管上皮细胞（HK-2细胞）中发挥肾毒性作用[50][51]。大黄素通过增强过氧化物酶体增殖物激活受体-γ（PPAR-γ）的表达，激活线粒体途径，引发细胞色素c（Cyt-c）释放、caspase-3活化和细胞周期阻滞，从而在HK-2细胞中诱导凋亡并降低细胞活力[52][53]。
Emodin exerts nephrotoxic effects in human renal proximal tubule epithelial cells (HK-2 cells) by enhancing the expression and stability of PPARγ, activating the mitochondrial pathway, and triggering caspase 3-dependent apoptosis < b1> [51] . Emodin activates the mitochondrial pathway by enhancing the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), triggering cytochrome c (Cyt-c) release, caspase-3 activation and cell cycle arrest, thereby Induces apoptosis and reduces cell viability in HK-2 cells [52] [53] .
2.2．芦荟大黄素的肾毒性机制
2.2． Mechanism of nephrotoxicity of aloe-emodin
芦荟大黄素通过内质网应激途径，诱导蛋白质错误折叠和钙离子平衡破坏，激活未折叠蛋白反应和caspase-1介导的凋亡，从而导致HK-2细胞的凋亡[54]。
Aloe-emodin induces protein misfolding and disruption of calcium ion balance through the endoplasmic reticulum stress pathway, activating the unfolded protein response and caspase-1-mediated apoptosis, thereby leading to apoptosis of HK-2 cells .
3.大黄酸的肾保护机制和肾毒性机制
3. Renal protection and nephrotoxicity mechanisms of rhein
3.1.大黄酸的肾保护机制
3.1. Renal protective mechanism of rhein
大黄酸的肾保护作用包括：减少尿白蛋白排泄，减轻肾小球肥大、系膜扩张和增殖，降低FN和TGF-β1的表达[55]。通过氧化应激减少肾脏脂褐素沉积，减少炎症因子的产生，通过阻断TNF-α/NF-κB信号通路抑制免疫应答，阻断肾间质纤维化的进展[56]。抑制TGF-β1的表达，减少IL-1、前列腺素E2、TNF等促炎细胞因子的合成[57]。调节Wnt/β-catenin通路、GSK3β、nephrin和PPAR-γ的表达改善肾损伤[58]。通过纠正Klotho基因启动子区域的超甲基化，显著上调Klotho蛋白表达，从而减轻肾纤维化[59][60]。通过调节AMPK依赖性mTOR信号通路以及Erk和p38 MAPKs信号通路抑制自噬，从而减轻肾纤维化[61]。通过促进Toll样受体4(TLR4)降解和恢复Klotho水平来减轻脂多糖（LPS）诱导的急性肾损伤[62]。通过激活SIRT3/FOXO3α信号通路，发挥抗氧化和抗纤维化作用，从而保护肾脏[63]。通过抑制lincRNA-Cox2/miR-150-5p/STAT1轴介导的炎性损伤，发挥对尿酸肾病的保护作用[64]。通过激活PPARα-CPT1A轴，调节脂肪酸氧化途径和脂质代谢，发挥肾保护作用[65]。通过保护Klotho蛋白、抑制促炎NF-κB信号通路和细胞因子的表达，从而减轻脂多糖诱导的急性肾损伤[66]。
The renal protective effects of rhein include: reducing urinary albumin excretion, reducing glomerular hypertrophy, mesangial expansion and proliferation, and reducing the expression of FN and TGF-β1 [55] . Reduce renal lipofuscin deposition through oxidative stress, reduce the production of inflammatory factors, inhibit immune response by blocking the TNF-α/NF-κB signaling pathway, and block the progression of renal interstitial fibrosis < b3>. Inhibit the expression of TGF-β1 and reduce the synthesis of pro-inflammatory cytokines such as IL-1, prostaglandin E2, and TNF [57] . Regulate the expression of Wnt/β-catenin pathway, GSK3β, nephrin and PPAR-γ to improve renal injury [58] . By correcting the hypermethylation of the Klotho gene promoter region, Klotho protein expression is significantly up-regulated, thereby alleviating renal fibrosis [59] [60] [61] . Alleviates lipopolysaccharide (LPS)-induced acute kidney injury by promoting Toll-like receptor 4 (TLR4) degradation and restoring Klotho levels [62] . By activating the SIRT3/FOXO3α signaling pathway, it exerts antioxidant and anti-fibrotic effects, thereby protecting the kidneys [ 63] . By inhibiting inflammatory damage mediated by the lincRNA-Cox2/miR-150-5p/STAT1 axis, it exerts a protective effect on uric acid nephropathy [64] . By activating the PPARα-CPT1A axis, it regulates the fatty acid oxidation pathway and lipid metabolism, exerting a renal protective effect [65] . By protecting Klotho protein and inhibiting the pro-inflammatory NF-κB signaling pathway and the expression of cytokines, it reduces lipopolysaccharide-induced acute kidney injury [66] .
3.2.大黄酸的肾毒性机制
3.2. Mechanism of nephrotoxicity of rhein
大黄酸的肾毒性机制包括：通过激活Fas依赖性凋亡通路，增强caspase-3和caspase-8的活性，并上调凋亡相关基因和蛋白的表达，从而发挥其肾毒性作用[67]。通过抑制UCP2、增加ROS生成以及激活线粒体介导的凋亡途径，从而在肾近曲小管上皮细胞中诱导凋亡，导致肾毒性[68]。通过降低线粒体膜电位（MMP）、减少ATP合成、增加ROS水平，以及抑制线粒体解偶联蛋白-2（UCP-2）的表达，显著加剧HK-2细胞的凋亡[69]。通过Fas途径和激活JNK及p38 MAPK信号通路，诱导HK-2细胞凋亡，表现出肾毒性[70]。
The nephrotoxic mechanism of rhein includes: activating the Fas-dependent apoptosis pathway, enhancing the activities of caspase-3 and caspase-8, and up-regulating the expression of apoptosis-related genes and proteins, thereby exerting its nephrotoxic effect . By inhibiting UCP2, increasing ROS production and activating the mitochondria-mediated apoptotic pathway, it induces apoptosis in renal proximal tubule epithelial cells, leading to nephrotoxicity [68] . Significantly aggravates the apoptosis of HK-2 cells by reducing mitochondrial membrane potential (MMP), reducing ATP synthesis, increasing ROS levels, and inhibiting the expression of mitochondrial uncoupling protein-2 (UCP-2) [69] . Through the Fas pathway and activation of the JNK and p38 MAPK signaling pathways, it induces apoptosis in HK-2 cells and exhibits nephrotoxicity [70] .
五、其他中药活性成分的肾毒性机制
5. Nephrotoxicity mechanism of other active ingredients of traditional Chinese medicine
1. 斑蝥素
1. Cantharidin
斑蝥素是斑蝥的主要生物活性成分，已被证实能够引起肾功能损伤、细胞毒性和细胞凋亡。研究表明，内质网应激相关的PERK/CHOP通路的激活，通过诱导自噬和凋亡，在大鼠和HK-2细胞中发挥毒性作用。基于HK-2细胞和大鼠模型的研究，斑蝥素通过触发内质网应激并激活自噬和凋亡，最终导致肾毒性[71]。
Cantharidin is the main bioactive component of Cantharidin and has been proven to cause renal function damage, cytotoxicity and apoptosis. Studies have shown that activation of the endoplasmic reticulum stress-related PERK/CHOP pathway exerts toxic effects in rats and HK-2 cells by inducing autophagy and apoptosis. Based on studies on HK-2 cells and rat models, cantharidin ultimately leads to nephrotoxicity [71] by triggering endoplasmic reticulum stress and activating autophagy and apoptosis.
2. 栀子苷
2. Geniposide
栀子及其主要成分对正常肝脏和肾脏会造成显著损伤，表现为抗氧化应激水平下降、细胞凋亡加速及大量炎性细胞因子的释放。中国药典推荐的栀子安全剂量为6-10克/天[72]。栀子的主要肾毒性成分是栀子苷，其肾毒性与抑制肾小管转运蛋白Oat1和Oat3有关。Oat1和Oat3主要分布于肾脏，特别是肾小管和肾上腺。Oat1和Oat3表达的减少会引发肾脏炎症，减少肾毒性物质的排泄，导致有机阴离子积累，最终造成肾脏损伤[73]。
Gardenia and its main components can cause significant damage to the normal liver and kidneys, manifested by decreased antioxidant stress levels, accelerated cell apoptosis, and the release of a large number of inflammatory cytokines. The safe dose of gardenia recommended by the Chinese Pharmacopoeia is 6-10 grams/day [72] . The main nephrotoxic component of gardenia is gardeniposide, and its nephrotoxicity is related to the inhibition of renal tubular transport proteins Oat1 and Oat3. Oat1 and Oat3 are mainly distributed in the kidneys, especially the renal tubules and adrenal glands. Reduced expression of Oat1 and Oat3 will trigger renal inflammation, reduce the excretion of nephrotoxic substances, lead to the accumulation of organic anions, and ultimately cause kidney damage [73] .
3.雄黄
3. Realgar
通过采用LC/Orbitrap Fusion Lumos HR-MS对雄黄暴露后小鼠肾脏进行蛋白质组学分析，结果显示雄黄以剂量依赖性的方式显著调控了272个蛋白，其中190个蛋白上调，82个蛋白下调。这些蛋白可能是雄黄致肾毒性的关键蛋白。GO分析结果证实，细胞凋亡和氧化应激是雄黄引起急性肾损伤的主要原因[74]。
Proteomic analysis of mouse kidneys after realgar exposure using LC/Orbitrap Fusion Lumos HR-MS showed that realgar significantly regulated 272 proteins in a dose-dependent manner, of which 190 proteins were up-regulated and 82 proteins were down-regulated. These proteins may be the key proteins in realgar-induced nephrotoxicity. GO analysis results confirmed that cell apoptosis and oxidative stress are the main causes of acute kidney injury caused by realgar [74] .
4.药根碱
4. Jatrorrhizine
Berberrubine (BRB，药根碱) 是小檗碱（Berberine）的代谢产物，存在于黄连和黄柏中。研究表明，BRB可能引起严重的肾毒性。通过蛋白质组学、代谢组学、细胞热稳定性分析（CETSA）和分子对接分析，结果表明ERK 1/2蛋白是BRB诱导肾毒性的直接结合靶点[75]。
Berberrubine (BRB, jatrorrhizine) is a metabolite of berberine and is found in coptis and phellodendron. Research shows that BRB may cause severe nephrotoxicity. Through proteomics, metabolomics, cellular thermal stability analysis (CETSA) and molecular docking analysis, the results show that ERK 1/2 protein is a direct binding target of BRB-induced nephrotoxicity [75]
5.穿心莲内酯
5. Andrographolide
穿心莲内酯显著抑制人肾小管上皮细胞（HK-2）的增殖，并以剂量和时间依赖性方式诱导细胞凋亡，降低超氧化物歧化酶（SOD）活性，增加丙二醛（MDA）含量。同时，内质网分子伴侣糖调节蛋白78（GRP78/BIP）、C/EBP同源蛋白（CHOP）和caspase-4的表达显著升高。因此，内质网应激和炎症反应可能是穿心莲内酯引起肾毒性的关键机制[76]。对26例由穿心莲内酯引起的急性肾损伤患者的分析显示，静脉注射穿心莲内酯后，患者出现腰痛、尿量减少、恶心或呕吐等副作用。病理研究表明，这些现象可能与急性管状细胞死亡有关[77]。
Andrographolide significantly inhibits the proliferation of human renal tubular epithelial cells (HK-2), induces apoptosis in a dose- and time-dependent manner, reduces superoxide dismutase (SOD) activity, and increases malondialdehyde (MDA) content. . At the same time, the expression of endoplasmic reticulum chaperone glycoregulatory protein 78 (GRP78/BIP), C/EBP homologous protein (CHOP) and caspase-4 was significantly increased. Therefore, endoplasmic reticulum stress and inflammatory response may be the key mechanisms of nephrotoxicity caused by andrographolide [76] . An analysis of 26 patients with acute kidney injury caused by andrographolide showed that after intravenous injection of andrographolide, patients experienced side effects such as low back pain, decreased urine output, nausea or vomiting. Pathological studies have shown that these phenomena may be related to acute tubular cell death [77] .
六、中药超剂量或长期服用诱导的肾毒性
6. Nephrotoxicity induced by excessive dosage or long-term use of traditional Chinese medicine
1．大黄
1. rhubarb
大黄在不同剂量水平下对肾脏的影响存在显著差异。在相当于临床剂量1.25倍的剂量下连续给药大鼠1个月，未见明显肾毒性。然而，在超高剂量（相当于临床剂量的10倍）下灌胃大鼠1个月，出现了一定程度的肾脏损伤。因此，临床用药时应合理控制剂量[78]。
There were significant differences in the effects of rhubarb on the kidneys at different dose levels. No obvious nephrotoxicity was found in rats after continuous administration for 1 month at a dose equivalent to 1.25 times the clinical dose. However, a certain degree of kidney damage occurred in rats administered intragastrically for 1 month at ultra-high doses (equivalent to 10 times the clinical dose). Therefore, the dosage should be controlled reasonably [78] during clinical use.
2．杜仲
2. Eucommia ulmoides
《中国药典》规定杜仲的临床常用剂量为8g/d。Lang等人报道，高达1200mg/kg的杜仲在大鼠中不会引起急性（24小时）或亚慢性（28天）毒性。即使在最大耐受剂量168g/kg时，杜仲也不会引起急性毒性。然而，长期服用相对高剂量（超过28g/kg）的杜仲会导致肾毒性，但停药后这种毒性会减轻[79]。
The "Chinese Pharmacopoeia" stipulates that the commonly used clinical dose of Eucommia ulmoides is 8g/d. Lang et al. reported that Eucommia ulmoides did not cause acute (24 hours) or subchronic (28 days) toxicity in rats at doses up to 1200 mg/kg. Even at the maximum tolerated dose of 168g/kg, Eucommia ulmoides does not cause acute toxicity. However, long-term use of relatively high doses (more than 28g/kg) of Eucommia ulmoides can cause nephrotoxicity, but this toxicity will be reduced after discontinuation of the drug [79] .
3．朱砂
3. cinnabar
朱砂含有重金属汞，长期使用会导致汞在肾脏内蓄积，进而造成肾脏损害[80]。大剂量的朱砂可引起急性肾功能损害。朱砂诱导的肾毒性机制主要通过肾小管上皮细胞凋亡实现，其中，死亡受体介导的凋亡信号通路是关键途径之一[81]。此外，汞还可以通过线粒体介导的内源性途径诱导细胞凋亡，通过增加线粒体膜的通透性影响ATP的合成，并导致细胞色素c的释放，进一步增强细胞氧化应激，最终引发细胞凋亡[82][83]。
Cinnabar contains the heavy metal mercury. Long-term use can cause mercury to accumulate in the kidneys, causing kidney damage [80] . Large doses of cinnabar can cause acute renal damage. The nephrotoxicity mechanism induced by cinnabar is mainly realized through the apoptosis of renal tubular epithelial cells, in which the death receptor-mediated apoptosis signaling pathway is one of the key pathways [81] . In addition, mercury can also induce cell apoptosis through the mitochondria-mediated endogenous pathway, affect the synthesis of ATP by increasing the permeability of the mitochondrial membrane, and lead to the release of cytochrome c, which further enhances cellular oxidative stress and ultimately triggers cellular Apoptosis [82] [83] .
七、中药活性成分改善顺铂诱导的肾毒性
7. Active ingredients of traditional Chinese medicine improve cisplatin-induced nephrotoxicity
目前用于预防和治疗顺铂（DDP）肾毒性的中药活性成分有黄酮类、生物碱类、多酚类、萜类、皂苷类和蒽醌类等。
The active ingredients of traditional Chinese medicine currently used to prevent and treat cisplatin (DDP) nephrotoxicity include flavonoids, alkaloids, polyphenols, terpenes, saponins and anthraquinones.
1.黄酮类
1. Flavonoids
槲皮素（quercetin）是一种常见的黄酮类化合物，具有抗炎和抗氧化等作用。研究表明，槲皮素能够在分子水平上显著降低顺铂引起的肾毒性。槲皮素通过降低血清肌酐和尿素水平，提高还原性谷胱甘肽（GSH）、维生素E和维生素C等非酶促抗氧化物质的含量，并在基因和蛋白质水平上诱导酶促抗氧化系统，从而发挥保护作用。槲皮素对顺铂所致肾损伤的保护作用可能与其强抗氧化特性有关[84]。
Quercetin is a common flavonoid compound that has anti-inflammatory and antioxidant effects. Studies have shown that quercetin can significantly reduce cisplatin-induced nephrotoxicity at the molecular level. Quercetin increases the content of non-enzymatic antioxidant substances such as reduced glutathione (GSH), vitamin E and vitamin C by reducing serum creatinine and urea levels, and induces the enzymatic antioxidant system at the gene and protein levels. , thus exerting a protective effect. The protective effect of quercetin on cisplatin-induced renal injury may be related to its strong antioxidant properties [84] .
芦丁（rutin）是一种天然黄酮类化合物，广泛存在于多种植物中。研究表明，ROS、caspase-3、NF-κB和TNF-α等凋亡通路蛋白在顺铂诱导的肾毒性发病机制中起重要作用，因此，芦丁通过调控这些通路蛋白，可能是预防顺铂诱导的肾损伤的有效策略[85]。
Rutin is a natural flavonoid compound that is widely present in a variety of plants. Studies have shown that apoptotic pathway proteins such as ROS, caspase-3, NF-κB and TNF-α play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. Therefore, rutin may be able to prevent cisplatin by regulating these pathway proteins. Effective strategies for induced renal injury [85] .
2.生物碱类
2.Alkaloids
小檗碱是从中药黄连、黄柏等小檗属植物根茎中提取得到，又称黄连素。小檗碱通过降低CYP2E1表达和抑制促炎NF-jB通路，对顺铂所致肾损伤表现出剂量依赖性的保护作用，因此小檗碱对顺铂所致肾损伤有肾保护作用[86]。
Berberine is extracted from the rhizomes of Berberis genus such as Coptis chinensis and Cortex Phellodendron, also known as berberine. Berberine shows a dose-dependent protective effect on cisplatin-induced renal injury by reducing CYP2E1 expression and inhibiting the pro-inflammatory NF-jB pathway. Therefore, berberine has a renal protective effect on cisplatin-induced renal injury [86] .
3.多酚类
3.Polyphenols
姜黄素是一种从姜科姜黄属植物中提取的天然多酚类化合物。研究表明，姜黄素能够通过清除活性氧（ROS）并以剂量依赖性方式改善肾脏氧化和亚硝基应激，显著降低血清TNF-α水平。此外，姜黄素能剂量依赖性地改善肌酐和尿素清除率，显著恢复肾功能，减少脂质过氧化反应，提高还原型谷胱甘肽的水平，并增强超氧化物歧化酶和过氧化氢酶的活性。因此，姜黄素可作为顺铂肾毒性的辅助治疗药物[87]。
Curcumin is a natural polyphenolic compound extracted from the Curcuma longa plant of the Zingiberaceae family. Studies have shown that curcumin can significantly reduce serum TNF-α levels by scavenging reactive oxygen species (ROS) and improving renal oxidative and nitroso stress in a dose-dependent manner. In addition, curcumin dose-dependently improved creatinine and urea clearance, significantly restored renal function, reduced lipid peroxidation, increased reduced glutathione levels, and enhanced superoxide dismutase and catalase activity. Therefore, curcumin can be used as an adjuvant treatment for cisplatin nephrotoxicity [87] .
4.蒽醌类
4 Anthraquinones
大黄素属于蒽醌类化合物。研究表明，大黄素通过调节AMPK/mTOR信号通路，激活自噬，改善顺铂诱导的体外大鼠肾小管细胞凋亡。因此，大黄素可能具有预防顺铂所致肾毒性的治疗潜力[88]。
Emodin belongs to the anthraquinone class of compounds. Studies have shown that emodin activates autophagy and improves cisplatin-induced apoptosis of rat renal tubular cells in vitro by regulating the AMPK/mTOR signaling pathway. Therefore, emodin may have therapeutic potential to prevent cisplatin-induced nephrotoxicity [88] .
5.五味子茎
5. Schisandra stems
五味子茎提取物（SCE）通过降低一氧化氮合酶（iNOS）和环氧合酶-2（COX-2）的表达，以及抑制核因子-κB（NF-κB）p65的激活，发挥抗炎作用。SCE还通过下调Bax和cleaved caspase-3、8、9的表达，并上调Bcl-2的表达，抑制凋亡通路的激活。因此，SCE通过抑制氧化应激、炎症和细胞凋亡，对顺铂诱导的肾毒性具有显著的治疗作用[89]。
Schisandra chinensis stem extract (SCE) exerts anti-inflammatory effects by reducing the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and inhibiting the activation of nuclear factor-κB (NF-κB) p65 effect. SCE also inhibits the activation of the apoptosis pathway by downregulating the expression of Bax and cleaved caspase-3, 8, and 9, and upregulating the expression of Bcl-2. Therefore, SCE has a significant therapeutic effect on cisplatin-induced nephrotoxicity by inhibiting oxidative stress, inflammation and apoptosis [89] .
6.人参皂苷Rg3和人参皂苷Rh1
6. Ginsenoside Rg3 and ginsenoside Rh1
人参皂苷Rg3（SY）是一种从人参中提取的活性成分。研究表明，SY能够减轻体内和体外顺铂诱导的肾损伤，表现为晚期凋亡细胞比例降低、线粒体膜电位升高和肾脏组织损伤改善。SY通过上调LC3II/I和beclin-1，抑制p62、NLRP3、ASC、caspase-1和白细胞介素-1β，从而改善CP（顺铂）诱导的肾损伤。SY通过激活自噬介导的NLRP3抑制途径减轻CP诱导的肾损伤[90]。
Ginsenoside Rg3 (SY) is an active ingredient extracted from ginseng. Studies have shown that SY can reduce cisplatin-induced renal injury in vivo and in vitro, which is manifested by a reduction in the proportion of late apoptotic cells, an increase in mitochondrial membrane potential, and an improvement in renal tissue damage. SY improves CP (cisplatin)-induced renal injury by upregulating LC3II/I and beclin-1 and inhibiting p62, NLRP3, ASC, caspase-1 and interleukin-1β. SY alleviates CP-induced renal injury by activating the autophagy-mediated NLRP3 inhibition pathway [90] .
人参皂苷Rh1是人参的主要成分之一。在顺铂诱导的肾损伤模型中，Rh1能够提高HK-2细胞的活力，抑制过量ROS的产生和HK-2细胞的凋亡，并抑制JNK、p53、caspase-3、Bax和NGAL蛋白的表达。通过抑制JNK/p53通路，Rh1能够显著减轻顺铂诱导的肾损伤[91]。
Ginsenoside Rh1 is one of the main components of ginseng. In the cisplatin-induced renal injury model, Rh1 can increase the viability of HK-2 cells, inhibit excessive ROS production and apoptosis of HK-2 cells, and inhibit the expression of JNK, p53, caspase-3, Bax and NGAL proteins . By inhibiting the JNK/p53 pathway, Rh1 can significantly reduce cisplatin-induced renal injury [91] .
7.甘草素
7.Liquiritin
甘草素可通过改善小鼠线粒体功能障碍和急性肾损伤，恢复肾小管和线粒体形态，降低血清肌酐（Scr）和血尿素氮（BUN）水平，并减少细胞凋亡。体内和体外实验均证实，甘草素能够诱导SIRT3的表达升高，而SIRT3的上调由NRF2介导。甘草素诱导NRF2的核移位，并增加了与NRF2活性和线粒体生物合成相关的蛋白质水平，如PGC-1α和TFAM。综上所述，甘草素通过NRF2/SIRT3通路改善线粒体功能，从而发挥对顺铂所致肾毒性的保护作用[92]。
Liquiritigenin can restore renal tubule and mitochondrial morphology, reduce serum creatinine (Scr) and blood urea nitrogen (BUN) levels, and reduce cell apoptosis by improving mitochondrial dysfunction and acute kidney injury in mice. Both in vivo and in vitro experiments have confirmed that liquiritigenin can induce an increase in the expression of SIRT3, and the upregulation of SIRT3 is mediated by NRF2. Liquiritigenin induces the nuclear translocation of NRF2 and increases the levels of proteins related to NRF2 activity and mitochondrial biogenesis, such as PGC-1α and TFAM. In summary, liquiritigenin improves mitochondrial function through the NRF2/SIRT3 pathway, thereby exerting a protective effect against cisplatin-induced nephrotoxicity [92] .
8.橙皮素
8. Hesperetin
陈皮中含有约11.4%的橙皮素[93]。研究表明，橙皮素可以减轻顺铂引起的肾毒性。在体外实验中，橙皮素显著降低顺铂处理的HK-2细胞中的ROS水平，从而减轻氧化应激诱导的细胞凋亡，同时激活Nrf2信号通路并调控其下游基因NQO1和HO-1。体内实验和肾脏组织病理学分析显示，与顺铂组相比，橙皮素组显著减轻了顺铂引起的肾毒性。肾组织的免疫印迹分析显示，橙皮素以剂量依赖性方式激活Nrf2，减弱MAPK信号通路的抗炎作用，并抑制凋亡蛋白的表达，从而保护肾脏免受顺铂引起的急性肾损伤（AKI）[94]。
Tangerine peel contains about 11.4% hesperetin [93] . Studies have shown that hesperetin can reduce cisplatin-induced nephrotoxicity. In in vitro experiments, hesperetin significantly reduced ROS levels in cisplatin-treated HK-2 cells, thereby alleviating oxidative stress-induced apoptosis, while activating the Nrf2 signaling pathway and regulating its downstream genes NQO1 and HO-1. In vivo experiments and renal histopathological analysis showed that compared with the cisplatin group, the hesperetin group significantly reduced the nephrotoxicity caused by cisplatin. Western blot analysis of kidney tissue showed that hesperetin activates Nrf2 in a dose-dependent manner, weakens the anti-inflammatory effect of the MAPK signaling pathway, and inhibits the expression of apoptotic proteins, thereby protecting the kidney from cisplatin-induced acute kidney injury (AKI). ) [94] .
9.双氢青蒿素(DHA)
9. Dihydroartemisinin (DHA)
双氢青蒿素（DHA）是从中药黄花蒿（Artemisia annua L.）中提取的青蒿素的活性衍生物。研究表明，DHA通过其抗炎和抗氧化活性改善脂多糖（LPS）诱导的小鼠急性肾损伤。DHA通过抑制NFκB p65调控的炎症反应，缓解p63介导的线粒体内源性和Fas死亡受体外源性凋亡通路，从而抑制顺铂诱导的肾细胞凋亡。综上所述，DHA通过减少炎症、氧化应激和细胞凋亡，预防顺铂引发的肾毒性[95]。
Dihydroartemisinin (DHA) is an active derivative of artemisinin extracted from the traditional Chinese medicine Artemisia annua L. Studies have shown that DHA improves lipopolysaccharide (LPS)-induced acute kidney injury in mice through its anti-inflammatory and antioxidant activities. DHA inhibits the inflammatory response regulated by NFκB p65 and relieves the p63-mediated mitochondrial endogenous and Fas death receptor extrinsic apoptosis pathways, thereby inhibiting cisplatin-induced renal cell apoptosis. In summary, DHA prevents cisplatin-induced nephrotoxicity [95] by reducing inflammation, oxidative stress and apoptosis.
八、中药及其活性成分改善环孢霉素A诱导的肾毒性
8. Traditional Chinese medicine and its active ingredients improve cyclosporine A-induced nephrotoxicity
1.冬虫夏草菌丝糖蛋白
1. Cordyceps sinensis mycelium glycoprotein
环孢霉素A（CsA）是预防肾移植排斥的重要免疫抑制剂，但长期使用可导致慢性肾毒性。研究发现，同时给予冬虫夏草菌丝糖蛋白（CSP）后，CsA损害的尿素和肌酐清除率显著改善。TUNEL组织化学染色显示，CSP显著减少了CsA引起的肾小管细胞凋亡。CSP通过增加镁重吸收通道TRPM6和TRPM7，恢复CsA诱导的镁流失，从而显著抑制CsA诱导的肾细胞凋亡，并对肾细胞损失具有保护作用。因此，冬虫夏草菌丝糖蛋白能够改善环孢霉素诱导的大鼠肾小管功能障碍[96]。
Cyclosporine A (CsA) is an important immunosuppressant for preventing renal transplant rejection, but long-term use can lead to chronic nephrotoxicity. The study found that CsA-impaired urea and creatinine clearance were significantly improved after concurrent administration of Cordyceps sinensis mycelial glycoprotein (CSP). TUNEL histochemical staining showed that CSP significantly reduced CsA-induced renal tubular cell apoptosis. CSP restores CsA-induced magnesium loss by increasing magnesium reabsorption channels TRPM6 and TRPM7, thereby significantly inhibiting CsA-induced renal cell apoptosis and having a protective effect on renal cell loss. Therefore, Cordyceps sinensis mycelium glycoprotein can improve cyclosporine-induced renal tubular dysfunction in rats [96] .
2. 黄芪和丹参
2. Astragalus and Salvia miltiorrhiza
黄芪和丹参通过“肠肾轴”改善环孢素A诱导的慢性肾毒性。丹参（AS）可通过“肠肾轴”通路减轻慢性肾毒性（CICN）引起的肾纤维化和代谢失调。研究表明，益生菌如Akkermansia和Lactobacillus是主要的驱动因素，而miRNA-mRNA相互作用谱，特别是丁酸代谢和色氨酸代谢可能是重要的调控机制[97]。
Astragalus and Salvia miltiorrhiza improve cyclosporine A-induced chronic nephrotoxicity through the "gut-kidney axis". Salvia miltiorrhiza (AS) can alleviate renal fibrosis and metabolic disorders caused by chronic nephrotoxicity (CICN) through the "gut-renal axis" pathway. Studies have shown that probiotics such as Akkermansia and Lactobacillus are the main driving factors, while miRNA-mRNA interaction profiles, especially butyrate metabolism and tryptophan metabolism, may be important regulatory mechanisms [97]
九、中药及其活性成分改善其他药物诱导的肾毒性
9. Traditional Chinese medicine and its active ingredients can improve nephrotoxicity induced by other drugs
1.人参皂苷Rb1改善补骨脂诱导的肾毒性
1. Ginsenoside Rb1 improves psoralen-induced nephrotoxicity
补骨脂二氢黄酮（bavachin, BV）是补骨脂中引起肾毒性的主要成分之一。研究表明，BV诱导的活性氧（ROS）主要通过Bip/eIF2α/chop介导的内质网应激，促进上皮-间质转化（EMT）和肾纤维化的发生。人参皂苷Rb1通过抑制ROS的产生和激活HK-2细胞中的Bip/eIF2α/chop信号传导，显著下调BV诱导的内质网应激，改善EMT和肾纤维化。因此，人参皂苷Rb1可以显著改善补骨脂引起的肾毒性[98]。
Bavachin (BV) is one of the main components of psoralen that causes nephrotoxicity. Studies have shown that BV-induced reactive oxygen species (ROS) promotes epithelial-to-mesenchymal transition (EMT) and renal fibrosis mainly through Bip/eIF2α/chop-mediated endoplasmic reticulum stress. Ginsenoside Rb1 significantly downregulates BV-induced endoplasmic reticulum stress and improves EMT and renal fibrosis by inhibiting ROS production and activating Bip/eIF2α/chop signaling in HK-2 cells. Therefore, ginsenoside Rb1 can significantly improve the nephrotoxicity caused by psoralen [98] .
2.酸枣仁改善布洛芬诱导的肾毒性
2. Ziziphus seed improves ibuprofen-induced nephrotoxicity
酸枣仁（Zizyphus jujuba Mill）长期被用于治疗焦虑和失眠。研究结果表明，枣仁水提物可以降低布洛芬引起的肾毒性作用[99]。
Zizyphus jujuba Mill has long been used to treat anxiety and insomnia. Research results show that jujube kernel aqueous extract can reduce the nephrotoxic effects caused by ibuprofen [99] .
3.五味子油改善AAI诱导的肾毒性
3 Schisandra chinensis oil improves AAI-induced nephrotoxicity
五味子油能够减轻马兜铃酸Ⅰ（AAⅠ）在体内和体外引起的肾损伤。其保护机制可能与调节代谢酶，从而抑制细胞凋亡和活性氧（ROS）的产生密切相关[100]。
Schisandra chinensis oil can reduce kidney damage caused by aristolochic acid I (AAI) in vivo and in vitro. Its protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and the generation of reactive oxygen species (ROS) [100] .
4．淫羊藿改善环磷酰胺诱导的肾毒性
4. Epimedium improves cyclophosphamide-induced nephrotoxicity
淫羊藿属植物的主要药用成分是淫羊藿茎叶总黄酮。研究表明，淫羊藿茎叶总黄酮能够减轻环磷酰胺引起的肾毒性。通过分子对接技术结合动物实验，研究提示淫羊藿总黄酮的有效成分可能通过激活Keap1-Nrf2信号通路，减轻环磷酰胺导致的肾组织炎症和氧化应激，从而减轻肾损伤[101]。
The main medicinal component of epimedium plants is total flavonoids from epimedium stems and leaves. Studies have shown that total flavonoids from epimedium stems and leaves can reduce nephrotoxicity caused by cyclophosphamide. Through molecular docking technology combined with animal experiments, research suggests that the active ingredients of epimedium total flavonoids may reduce renal tissue inflammation and oxidative stress caused by cyclophosphamide by activating the Keap1-Nrf2 signaling pathway, thereby reducing renal damage .
5．姜黄素改善黄曲霉毒素B1诱导的肾毒性
5. Curcumin improves aflatoxin B1-induced nephrotoxicity
姜黄素可减轻黄曲霉毒素B1（AFB1）诱导的雏鸭肾脏畸形。研究表明，姜黄素通过降低氧化损伤标志物丙二醛（MDA）和8-羟基-2脱氧鸟苷（8-OHdG）的表达水平，改善线粒体相关抗氧化酶和Nrf2通路的表达，从而抑制黄曲霉毒素B1诱导的线粒体介导的氧化应激。值得注意的是，姜黄素减少了肾脏中的铁积累，通过NCOA4途径抑制了铁蛋白的自噬，平衡了铁的稳态，从而减轻了黄曲霉毒素B1诱导的肾铁凋亡。总之，姜黄素通过抑制线粒体介导的氧化应激、铁蛋白自噬和铁凋亡，有效减轻了AFB1诱导的雏鸭肾毒性[102]。
Curcumin can alleviate aflatoxin B1 (AFB1)-induced renal malformations in ducklings. Studies have shown that curcumin reduces the expression levels of oxidative damage markers malondialdehyde (MDA) and 8-hydroxy-2 deoxyguanosine (8-OHdG), improves the expression of mitochondria-related antioxidant enzymes and the Nrf2 pathway, thereby inhibiting yellow Mitochondria-mediated oxidative stress induced by aspergillus toxin B1. Notably, curcumin reduced iron accumulation in the kidney, inhibited ferritin autophagy through the NCOA4 pathway, and balanced iron homeostasis, thereby alleviating aflatoxin B1-induced renal ferroptosis. In conclusion, curcumin effectively alleviated AFB1-induced nephrotoxicity in ducklings [102] by inhibiting mitochondria-mediated oxidative stress, ferritin autophagy and ferroptosis.
总结
Summarize
综上所述，中药在肾脏方面展现出显著的双重作用，既具有肾毒性，又具备肾保护作用。这些研究为中药的安全性评估提供了重要依据，并为其在临床治疗中的合理应用提供了科学指导。尽管中药肾毒性的研究取得了显著进展，但其肾保护作用的机制仍需进一步深入的系统性研究和临床验证。未来的研究应重点关注以下几个方面：1.中药的剂量效应：探讨不同剂量下中药的肾毒性与肾保护作用的差异。2.影响因素研究：分析同时具有肾毒性和肾保护作用的中药，其毒性和保护作用受哪些因素影响。3.分子调控路径：探讨中药在药物诱导肾毒性和肾保护作用的分子水平上的调控机制。这些努力将有助于全面、客观地评估中药在现代医学中的治疗潜力，为患者提供更安全、更有效的治疗选择。
In summary, traditional Chinese medicine exhibits significant dual effects on the kidneys, being both nephrotoxic and nephroprotective. These studies provide an important basis for the safety evaluation of traditional Chinese medicines and provide scientific guidance for their rational application in clinical treatment. Although the research on nephrotoxicity of traditional Chinese medicine has made significant progress, the mechanism of its nephroprotective effect still requires further in-depth systematic research and clinical verification. Future research should focus on the following aspects: 1. Dose effect of traditional Chinese medicine: explore the differences in nephrotoxicity and renal protective effects of traditional Chinese medicine at different doses. 2. Research on influencing factors: Analyze the factors that affect the toxicity and protective effects of traditional Chinese medicines that have both nephrotoxic and nephroprotective effects. 3. Molecular regulatory pathways: Explore the regulatory mechanisms of traditional Chinese medicine on the molecular level of drug-induced nephrotoxicity and nephroprotective effects. These efforts will help to comprehensively and objectively evaluate the therapeutic potential of traditional Chinese medicine in modern medicine and provide patients with safer and more effective treatment options.
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