Ansari Mushtaq Ahmad, Raish Mohammad, Ahmad Ajaz, Alkharfy Khalid M, Ahmad Sheikh Fayaz, Attia Sabry M, Alsaad Abdulaziz M S, Bakheet Saleh A
Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
Environ Toxicol Pharmacol. 2017 Apr;51:100-107. doi: 10.1016/j.etap.2017.02.014. Epub 2017 Feb 15.
Cadmium (CD), an environmental and industrial pollutant, generates reactive oxygen species (ROS) and NOS responsible for oxidative and nitrosative stress that can lead to nephrotoxic injury, including proximal tubule and glomerulus dysfunction. Sinapic acid (SA) has been found to possess potent antioxidant and anti-inflammatory effects in vitro and in vivo. We aimed to examine the nephroprotective, anti-oxidant, anti-inflammatory, and anti-apoptotic effects of SA against CD-induced nephrotoxicity and its underlying mechanism. Kidney functional markers (serum urea, uric acid, creatinine, LDH, and calcium) and histopathological examinations of the kidney were used to evaluate CD-induced nephrotoxicity. Oxidative stress markers (lipid peroxidation and total protein), renal nitrosative stress (nitric oxide), antioxidant enzymes (catalase and NP-SH), inflammation markers (NF-κB [p65], TNF-α, IL-6, and myeloperoxidase [MPO]), and apoptotic markers (caspase 3, Bax, and Bcl-2) were also assessed. SA (10 and 20mg/kg) pretreatment restored kidney function, upregulated antioxidant levels, and prevented the elevation of lipid peroxidation and nitric oxide levels, significantly reducing oxidative and nitrosative stress. CD upregulated renal cytokine levels (TNF-α, IL-6), nuclear NF-κB (p65) expression, NF-κB-DNA-binding activity, and MPO activity, which were significantly downregulated upon SA pretreatment. Furthermore, SA treatment prevented the upregulation of caspase 3 and Bax protein expression and upregulated Bcl-2 protein expression. SA pretreatment also alleviated the magnitude of histological injuries and reduced neutrophil infiltration in renal tubules. We conclude that the nephroprotective potential of SA in CD-induced nephrotoxicity might be due to its antioxidant, anti-inflammatory, and anti-apoptotic potential via downregulation of oxidative/nitrosative stress, inflammation, and apoptosis in the kidney.
镉（Cd）是一种环境和工业污染物，可产生活性氧（ROS）和一氧化氮合酶（NOS），导致氧化应激和亚硝化应激，进而引发肾毒性损伤，包括近端肾小管和肾小球功能障碍。已发现芥子酸（SA）在体外和体内均具有强大的抗氧化和抗炎作用。我们旨在研究SA对Cd诱导的肾毒性的肾保护、抗氧化、抗炎和抗凋亡作用及其潜在机制。通过检测肾功能标志物（血清尿素、尿酸、肌酐、乳酸脱氢酶和钙）以及肾脏组织病理学检查来评估Cd诱导的肾毒性。还评估了氧化应激标志物（脂质过氧化和总蛋白）、肾脏亚硝化应激（一氧化氮）、抗氧化酶（过氧化氢酶和非蛋白巯基）、炎症标志物（核因子κB [p65]、肿瘤坏死因子-α、白细胞介素-6和髓过氧化物酶 [MPO]）以及凋亡标志物（半胱天冬酶3、Bax和Bcl-2）。SA（10和20mg/kg）预处理可恢复肾功能，上调抗氧化水平，并防止脂质过氧化和一氧化氮水平升高，显著降低氧化应激和亚硝化应激。Cd上调了肾脏细胞因子水平（肿瘤坏死因子-α、白细胞介素-6）、核因子κB（p65）表达、核因子κB-DNA结合活性和MPO活性，而SA预处理后这些指标均显著下调。此外，SA处理可防止半胱天冬酶3和Bax蛋白表达上调，并上调Bcl-2蛋白表达。SA预处理还减轻了组织学损伤的程度，并减少了肾小管中的中性粒细胞浸润。我们得出结论，SA对Cd诱导的肾毒性的肾保护潜力可能归因于其通过下调肾脏中的氧化/亚硝化应激、炎症和凋亡所具有的抗氧化、抗炎和抗凋亡潜力。
