Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Toxicol Mech Methods. 2023 Nov;33(6):452-462. doi: 10.1080/15376516.2023.2177218. Epub 2023 Feb 22.
Despite the great importance of amphotericin B for the management of life-threatening systemic fungal infections, its nephrotoxic effect restricts its repeated administration. This study was designed to examine the prospective modulatory effects of xanthenone, an ACE2 activator, against amphotericin B nephrotoxicity. Male Wistar rats were allocated into four groups; control (1), Xanthenone (2), Amphotericin B (3), and Xanthenone + Amphotericin B (4). The second and fourth groups received xanthenone (2 mg/kg; s.c.) daily for 14 consecutive days. Amphotericin B (18.5 mg/kg; i.p.) was administered to the third and fourth groups daily starting from day 8. After 2 weeks, samples were withdrawn for analysis. The histopathological findings, molecular and biochemical markers showed that amphotericin B caused marked renal injury. Pretreatment with xanthenone ameliorated amphotericin B-induced deterioration in kidney function biomarkers (creatinine, urea, cystatin C, KIM-1) and guarded against the disturbance of serum electrolytes (Na, K, Mg) due to amphotericin B-induced tubular dysfunction. Besides, the ACE2 activator xanthenone-balanced renal Ang-II/Ang-(1-7), and so the inflammatory signaling p38 MAPK/NF-κB p65 and its downstream inflammatory cytokines (TNF-α, IL-6) were attenuated. Meanwhile, the anti-oxidant signaling Nrf2/HO-1 and glutathione content were preserved, but the lipid peroxidation marker MDA was declined. These regulatory effects of xanthenone eventually enhanced Bcl-2 (anti-apoptotic), but reduced Bax (pro-apoptotic) and cleaved caspase-3 (apoptotic executioner) protein expressions. Collectively, the regulatory effects of xanthenone on renal Ang-II/Ang-(1-7) could at least partially contribute to the mitigation of amphotericin B nephrotoxicity by attenuating inflammatory signaling, oxidative stress, and apoptosis, thus improving the tolerability to amphotericin B.
尽管两性霉素 B 对于治疗危及生命的系统性真菌感染非常重要，但它的肾毒性限制了其重复给药。本研究旨在研究黄烷酮（一种 ACE2 激活剂）对两性霉素 B 肾毒性的前瞻性调节作用。雄性 Wistar 大鼠分为四组；对照组（1）、黄烷酮（2）、两性霉素 B（3）和黄烷酮+两性霉素 B（4）。第二和第四组连续 14 天每天皮下注射黄烷酮（2mg/kg）。从第 8 天开始，第三和第四组每天腹腔注射两性霉素 B（18.5mg/kg）。2 周后，提取样本进行分析。组织病理学发现、分子和生化标志物表明，两性霉素 B 导致了明显的肾损伤。预先用黄烷酮处理可改善两性霉素 B 引起的肾功能生物标志物（肌酐、尿素、胱抑素 C、KIM-1）恶化，并防止由于两性霉素 B 引起的肾小管功能障碍而导致血清电解质（Na、K、Mg）紊乱。此外，ACE2 激活剂黄烷酮平衡了肾脏中的 Ang-II/Ang-（1-7），从而减轻了炎症信号 p38 MAPK/NF-κB p65 及其下游炎症细胞因子（TNF-α、IL-6）。同时，保留了抗氧化信号 Nrf2/HO-1 和谷胱甘肽含量，但降低了脂质过氧化标志物 MDA。黄烷酮的这些调节作用最终增强了 Bcl-2（抗凋亡），但减少了 Bax（促凋亡）和 cleaved caspase-3（凋亡执行者）蛋白表达。总之，黄烷酮对肾脏 Ang-II/Ang-（1-7）的调节作用至少部分有助于通过减轻炎症信号、氧化应激和凋亡来减轻两性霉素 B 的肾毒性，从而提高对两性霉素 B 的耐受性。
