Alhazzani Khalid, Alqarni Naif N, Aljerian Khaldoon, Raish Mohammad, Aljuffali Lobna, Alshehri Samiyah, Alanazi Ahmed Z
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Int J Med Sci. 2025 Jan 1;22(1):110-120. doi: 10.7150/ijms.102088. eCollection 2025.
Nephrotoxicity remains a significant concern associated with tyrosine kinase inhibitors, such as dasatinib (DASA). Previous studies have shown that DASA can induce renal tubular cell death, contributing to its nephrotoxic effects. In contrast, naringenin (NGN) is known for its antioxidant and anti-inflammatory properties. This study aimed to explore the nephroprotective potential of NGN against acute kidney injury induced by DASA in a mouse model. Mice were pre-treated with different doses of NGN (50, 100 mg/kg) for one week, followed by a single dose of DASA (25 mg/kg) on the 8th day. Results demonstrated that DASA significantly increased serum levels of blood urea nitrogen, creatinine, uric acid, and lactate dehydrogenase, which were effectively attenuated by NGN pretreatment. Furthermore, kidney tissues exposed to DASA exhibited elevated malondialdehyde (MDA) levels, which were significantly reduced by NGN. NGN also restored depleted levels of antioxidants (glutathione (GSH) and catalase (CAT)) in kidney tissues following DASA treatment. Additionally, NGN mitigated the upregulation of pro-inflammatory cytokines (TNF-α, NF-κB, and IL-6) induced by DASA, indicating an anti-inflammatory effect. Notably, DASA treatment upregulated the gene expression of the pro-apoptotic gene BAX while downregulating the expression of BCL-2 and Caspase-3 in kidney tissues. These findings suggest that NGN exerts nephroprotective effects against DASA-induced nephrotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. Further investigations are warranted to elucidate the underlying mechanisms involved.
肾毒性仍然是与酪氨酸激酶抑制剂（如达沙替尼，DASA）相关的一个重大问题。先前的研究表明，DASA可诱导肾小管细胞死亡，这与其肾毒性作用有关。相比之下，柚皮素（NGN）以其抗氧化和抗炎特性而闻名。本研究旨在探讨NGN对DASA诱导的小鼠急性肾损伤的肾保护潜力。小鼠用不同剂量的NGN（50、100mg/kg）预处理一周，然后在第8天给予单剂量的DASA（25mg/kg）。结果表明，DASA显著提高了血清中尿素氮、肌酐、尿酸和乳酸脱氢酶的水平，而NGN预处理有效地减弱了这些指标的升高。此外，暴露于DASA的肾组织中丙二醛（MDA）水平升高，而NGN显著降低了该水平。NGN还恢复了DASA处理后肾组织中耗尽的抗氧化剂（谷胱甘肽（GSH）和过氧化氢酶（CAT））水平。此外，NGN减轻了DASA诱导的促炎细胞因子（TNF-α、NF-κB和IL-6）的上调，表明其具有抗炎作用。值得注意的是，DASA处理上调了肾组织中促凋亡基因BAX的表达，同时下调了BCL-2和Caspase-3的表达。这些发现表明NGN通过其抗氧化、抗炎和抗凋亡特性对DASA诱导的肾毒性发挥肾保护作用。有必要进行进一步的研究以阐明其中涉及的潜在机制。
