Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, PR China.
Hunan Engineering Research Center of Livestock and Poultry Health Care, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, PR China; Institute of Yunnan Circular Agricultural Industry, Puer 665000, PR China.
Ecotoxicol Environ Saf. 2024 Oct 1;284:116946. doi: 10.1016/j.ecoenv.2024.116946. Epub 2024 Aug 28.
Citrinin (CTN) has been reported to induce renal failure and structural damage, but its nephrotoxic effects and mechanisms are not fully understood. Therefore, we established a model by orally administering CTN (0, 1.25, 5, or 20 mg/kg) to mice for 21 consecutive days. Histological and biochemical analyses revealed that CTN caused structural damage to renal tubules, increased inflammatory cell infiltration, and elevated levels of serum markers of renal function (creatinine, urea, and uric acid). Moreover, mRNA transcript levels of the inflammatory factors TNF-α, IL-1β, and IL-6 were increased, indicating the occurrence of an inflammatory response. Furthermore, exposure to CTN induced renal oxidative stress by decreasing antioxidant GSH levels, antioxidant enzyme (SOD, CAT) activities, and increasing oxidative products (ROS, MDA). In addition, CTN increased the expression of proteins associated with endoplasmic reticulum (ER)stress and apoptotic pathways. ER stress has been shown to be involved in regulating various models of kidney disease, but its role in CTN-induced renal injury has not been reported. We found that pretreatment with the ER stress inhibitor 4-PBA (240 mg/kg, ip) alleviated CTN-induced oxidative stress, NF-κB pathway mediated inflammatory response, and apoptosis. Interestingly, 4-PBA also partially alleviated renal structural damage and dysfunction. Thus, ER stress may be a novel target for the prevention and treatment of CTN-induced renal injury.
桔青霉素（CTN）已被报道可诱导肾衰竭和结构损伤，但它的肾毒性作用和机制尚未完全阐明。因此，我们通过连续 21 天给小鼠口服 CTN（0、1.25、5 或 20mg/kg）建立了一个模型。组织学和生化分析显示，CTN 导致肾小管结构损伤，炎症细胞浸润增加，肾功能血清标志物（肌酐、尿素和尿酸）水平升高。此外，促炎因子 TNF-α、IL-1β 和 IL-6 的 mRNA 转录水平升高，表明发生了炎症反应。此外，CTN 通过降低抗氧化剂 GSH 水平、抗氧化酶（SOD、CAT）活性和增加氧化产物（ROS、MDA）诱导肾脏氧化应激。此外，CTN 增加了与内质网（ER）应激和凋亡途径相关的蛋白质的表达。已经表明 ER 应激参与调节各种肾脏疾病模型，但尚未报道其在 CTN 诱导的肾损伤中的作用。我们发现，内质网应激抑制剂 4-PBA（240mg/kg，ip）预处理可减轻 CTN 诱导的氧化应激、NF-κB 途径介导的炎症反应和凋亡。有趣的是，4-PBA 还部分减轻了肾脏结构损伤和功能障碍。因此，内质网应激可能是预防和治疗 CTN 诱导的肾损伤的一个新靶点。
