Key Takeaways & Executive Findings
- •• Agrimol B protects against cisplatin-induced acute kidney injury by activating the Sirt1/Nrf2 signaling pathway, reducing oxidative stress and renal damage. • Network pharmacology identified Sirt1 as a critical target of agrimol B, and experimental validation confirmed its role in mediating renoprotective effects. • Agrimol B synergizes with cisplatin in antitumor activity, suggesting it may be a safe adjunct to chemotherapy without compromising efficacy. • These findings highlight agrimol B as a promising therapeutic candidate for preventing cisplatin-induced nephrotoxicity in clinical settings.
Abstract
Cisplatin (CDDP) is a widely used chemotherapeutic agent that has remarkable antineoplastic effects. However, CDDP can cause severe acute kidney injury (AKI), which limits its clinical application. Agrimol B is the main active ingredient found in Agrimonia pilosa Ledeb and has a variety of pharmacological activities. The effect of agrimol B on CDDP-induced renal toxicity has not been determined. To investigate whether agrimol B has a protective effect against CDDP-induced AKI, we first identify Sirtuin 1 (Sirt1) as a critical target protein of agrimol B in regulating AKI through network pharmacology analysis. Subsequently, the AKI mouse model is induced by administering a single dose of CDDP via intraperitoneal injection. By detecting the serum urea nitrogen and creatinine levels, as well as the histopathological changes, we confirm that agrimol B effectively reduces CDDP-induced AKI. In addition, treatment with agrimol B counteracts the increase in renal malondialdehyde level and the decrease in superoxide dismutase (SOD), catalase and glutathione levels induced by CDDP. Moreover, western blot results reveal that agrimol B upregulates the expressions of Sirt1, SOD2, nuclear factor erythroid2-related factor 2, and downstream molecules, including heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1. However, administration of the Sirt1 inhibitor EX527 abolishes the effects of agrimol B. Finally, we establish a tumor-bearing mouse model and find that agrimol B has a synergistic antitumor effect with CDDP. Overall, agrimol B attenuates CDDP-induced AKI by activating the Sirt1/Nrf2 signaling pathway to counteract oxidative stress, suggesting that this compound is a potential therapeutic agent for the treatment of CDDP-induced AKI.
1. Introduction
Cisplatin (CDDP) is a platinum-based chemotherapeutic agent that has been widely used to treat various malignant solid tumors, including testicular cancer, ovarian cancer, non-small cell lung cancer, cervical cancer, head and neck cancer, bladder cancer and gastric cancer [1,2]. Despite its potent antineoplastic effects, CDDP also has a variety of side effects, especially nephrotoxicity, which is the principal factor limiting its use and efficacy [3]. Approximately 25%‒30% of patients treated with CDDP progress to acute kidney injury (AKI), which is characterized by a rapid loss of kidney function and is associated with high morbidity and mortality [4]. The incidence of chronic kidney disease is also significantly increased in patients who survive AKI induced by CDDP [5]. At present, there is still no effective method to prevent or treat CDDP-induced AKI.
The mechanism of CDDP-induced AKI is very complex, and a lot of studies have shown that oxidative stress, inflammation, apoptosis, and DNA damage are involved in its pathogenesis [3,6]. In particular, CDDP is hydrolyzed within proximal tubule cells, and its products bind to intracellular antioxidants, resulting in the depletion and inactivation of antioxidants. This, in turn, leads to the abnormal accumulation of reactive oxygen species (ROS), ultimately damaging cellular structures and various components, such as DNA, proteins, and cell membranes [3,5]. The production of ROS causes the decrease of renal blood flow and tubular lesions. Additionally, it induces cell necrosis by promoting lipid peroxidation of cell membranes and DNA damage [7]. Therefore, alleviating oxidative stress is considered a potential strategy to improve CDDP-induced AKI.
Based on preclinical findings, the use of antioxidant components in natural products appears to be a promising approach for preventing CDDP-induced AKI without compromising antitumor activity [8]. The traditional Chinese medicine Agrimonia pilosa Ledeb, listed in the Pharmacopoeia of the People’s Republic of China, has antineoplastic, antioxidative, anti-inflammatory, and antihyperglycemic effects [9‒11]. Agrimol B, one of the main active ingredients, has also been shown to mitigate oxidative stress and counteract various types of cancers [11]. However, it remains unclear whether agrimol B has the potential to protect against CDDP-induced AKI.
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Jiarui Tang, Longhui Li, Zhijian Chen, Cuiting Liao, Kai Hu, Yongqiang Yang, Jiayi Huang, Li Tang, Li Zhang, Longjiang Li (2026). Agrimol B alleviates cisplatin-induced acute kidney injury by activating the Sirt1/Nrf2 signaling pathway in mice. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2023285
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that agrimol B alleviates cisplatin-induced acute kidney injury in mice by activating the Sirt1/Nrf2 signaling pathway, which counteracts oxidative stress and reduces renal damage.
How does agrimol B protect against cisplatin-induced nephrotoxicity?
Agrimol B activates the Sirt1/Nrf2 pathway, leading to upregulation of antioxidant enzymes such as SOD2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1, thereby reducing oxidative stress and preserving kidney function.
Does agrimol B interfere with the antitumor effect of cisplatin?
No, the study found that agrimol B has a synergistic antitumor effect with cisplatin, suggesting it can be used as an adjunct to chemotherapy without compromising efficacy.
What experimental models were used in this study?
The researchers used a mouse model of cisplatin-induced acute kidney injury and a tumor-bearing mouse model to evaluate both nephroprotective and antitumor effects.
What is the significance of identifying Sirt1 as a target of agrimol B?
Identifying Sirt1 as a critical target provides a mechanistic basis for the renoprotective effects of agrimol B and highlights a potential therapeutic strategy for preventing cisplatin-induced kidney injury.
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