Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Department of Pharmacology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt.
Life Sci. 2021 Jun 15;275:119387. doi: 10.1016/j.lfs.2021.119387. Epub 2021 Mar 24.
Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression through the classic ACE/Ang-II/AT1 axis and its antagonist, ACE2/Ang-(1-7)/Mas axis which exerts an important role in the kidney. The present study evaluates the protective effects of the angiotensin-converting enzyme 2 (ACE2) activator; xanthenone; against experimental nephrotoxicity induced by gentamicin. Rats were divided into 4 groups, normal control, xanthenone (2 mg/kg, s.c), gentamicin (100 mg/kg, i.p. for one week) and xanthenone + gentamicin groups. Blood urea nitrogen (BUN) and serum creatinine levels were measured. The kidney tissues were used for estimating glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB, Angiotensin II (AngII), and Ang-(1-7). In addition, histopathological examination and Western blot analysis of ACE2 expression were done. Xanthenone significantly restored serum levels of BUN and creatinine. Xanthenone exerted significant antioxidant effect as revealed by increased GSH content and SOD activity together with reduced MDA content. It exerted anti-inflammatory effect by significant reduction in TNF-α, NF-κB and IL-6 expression compared to gentamicin group. Xanthenone increased Ang-(1-7) and ACE2 expression while significantly decreased Ang-II expression. Histopathologically, xanthenone markedly counteracted gentamicin-induced renal aberrations. Activation of ACE2/Ang-(1-7) by xanthenone produced significant antioxidant and anti-inflammatory effects that counteracted gentamicin-induced nephrotoxicity.
肾毒性是由于接触庆大霉素等肾毒性药物而导致的肾功能迅速恶化。庆大霉素会增加活性氧（ROS）的产生，从而导致炎症反应和核因子-κB（NF-κB）的激活。肾素-血管紧张素系统（RAS）被认为是通过经典的 ACE/Ang-II/AT1 轴及其拮抗剂 ACE2/Ang-(1-7)/Mas 轴调节生理稳态和疾病进展的关键调节剂，该轴在肾脏中发挥重要作用。本研究评估了血管紧张素转换酶 2（ACE2）激活剂香豆素对庆大霉素诱导的实验性肾毒性的保护作用。大鼠分为 4 组，正常对照组、香豆素（2mg/kg，皮下注射）、庆大霉素（100mg/kg，腹腔注射一周）和香豆素+庆大霉素组。测定血尿素氮（BUN）和血清肌酐水平。肾组织用于估计谷胱甘肽（GSH）、超氧化物歧化酶（SOD）、丙二醛（MDA）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、NF-κB、血管紧张素 II（AngII）和 Ang-(1-7)。此外，还进行了 ACE2 表达的组织病理学检查和 Western blot 分析。香豆素显著恢复了血清 BUN 和肌酐水平。香豆素通过增加 GSH 含量和 SOD 活性以及降低 MDA 含量发挥显著的抗氧化作用。与庆大霉素组相比，它通过显著减少 TNF-α、NF-κB 和 IL-6 的表达发挥抗炎作用。香豆素增加了 Ang-(1-7)和 ACE2 的表达，同时显著降低了 Ang-II 的表达。组织病理学检查表明，香豆素明显逆转了庆大霉素引起的肾脏异常。香豆素激活 ACE2/Ang-(1-7)产生了显著的抗氧化和抗炎作用，可拮抗庆大霉素引起的肾毒性。
