Drug and Chemical Toxicology ( IF 2.6 ) Pub Date : 2020-02-03 , DOI: 10.1080/01480545.2020.1722156 Mohammad Dallak 1 , Amal F Dawood 2, 3 , Mohamed A Haidara 1, 3 , Dina H Abdel Kader 4 , Refaat A Eid 5 , Samaa S Kamar 4 , Asmaa M Shams Eldeen 3 , Bahjat Al-Ani 1
Abstract
Acute renal failure induced by a toxic dose of acetaminophen (also known as paracetamol, or APAP) is common in both humans and experimental animal models. Glomerular ultrastructural alterations induced by APAP overdose associated with the suppression of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced nephrotoxicity. Rats either received a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pretreated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. APAP significantly (p < 0.05) increased blood levels of urea, creatinine, malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which were effectively reduced by RES + QUR. In addition, APAP overdose induced the tissue expression of the apoptotic biomarker, p53, and caused profound kidney damage as demonstrated by substantial alterations to the glomerular basement membrane, podocytes, endothelial cells, widening of Bowman’s space, and vacuolation of the cells lining the parietal layer, which were substantially protected by RES + QUR. Furthermore, a significant (p < 0.0001) positive correlation was observed between either glomerular basement membrane or podocyte foot processes and these parameters, urea, creatinine, MDA, and TNF-α. Thus, we conclude that APAP induces alterations to the glomerulus ultrastructure, which is protected by resveratrol plus quercetin, which also reduces blood levels of urea and creatinine, and biomarkers of oxidative stress and inflammation.
中文翻译:
白藜芦醇和槲皮素联合使用抑制对乙酰氨基酚毒性引起的肾小球损伤和细胞凋亡以及急性肾损伤的生物标志物
摘要
由毒性剂量的对乙酰氨基酚(也称为扑热息痛,或 APAP)引起的急性肾功能衰竭在人类和实验动物模型中都很常见。与抑制肾损伤生物标志物相关的 APAP 过量诱导的肾小球超微结构改变以前没有被研究过。此外,我们还研究了联合多酚类抗氧化剂和抗炎化合物、白藜芦醇 (RES) 和槲皮素 (QUR) 是否可以防止 APAP 诱导的肾毒性。大鼠要么在 24 小时后处死前接受单剂量的 APAP (2 g/kg),要么在给予单剂量之前用 RES (30 mg/kg) 和 QUR (50 mg/kg) 的联合剂量预处理 7 天剂量的 APAP,然后在 APAP 摄入后 24 小时处死。APAP显着(p < 0.05) 增加尿素、肌酐、丙二醛 (MDA)、白细胞介素 6 (IL-6) 和肿瘤坏死因子-α (TNF-α) 的血液水平,RES + QUR 可有效降低这些水平。此外,APAP 过量会诱导凋亡生物标志物 p53 的组织表达,并导致严重的肾脏损伤,如肾小球基底膜、足细胞、内皮细胞的显着改变、Bowman 空间的扩大和壁层细胞的空泡化所示。层,基本上受到 RES + QUR 的保护。此外,显着的 ( p < 0.0001) 在肾小球基底膜或足细胞足突与这些参数尿素、肌酐、MDA 和 TNF-α 之间观察到正相关。因此,我们得出结论,APAP 诱导了肾小球超微结构的改变,该超微结构受到白藜芦醇和槲皮素的保护,这也降低了尿素和肌酐的血液水平,以及氧化应激和炎症的生物标志物。