Zhang Kanglei, Li Jiahui, Dong Wenxuan, Huang Qing, Wang Xueru, Deng Kai, Ali Waseem, Song Ruilong, Zou Hui, Ran Di, Liu Gang, Liu Zongping
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.
Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China.
Antioxidants (Basel). 2024 Apr 26;13(5):525. doi: 10.3390/antiox13050525.
Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade.
鸡是人类食物中肉类和蛋类的主要来源，具有重要的经济价值。镉（Cd）是一种常见的环境污染物，可污染饲料和饮用水，主要通过诱导自由基的产生，导致畜禽肾脏损伤。开发预防和治疗家禽镉诱导的肾毒性的潜在药物很有必要。木犀草素（Lut）是一种主要从花生壳中提取的天然黄酮类化合物，具有多种防御氧化损伤的生物学功能。在本研究中，我们旨在证明Lut是否能减轻镉暴露下的肾脏损伤，并阐明其潜在的分子机制。观察了肾脏组织病理学和细胞形态。分析了肾功能、氧化应激、DNA损伤与修复、NAD含量、SIRT1活性和自噬的指标。体外数据显示，镉暴露增加了ROS水平，诱导了氧化DNA损伤与修复，表现为8-OHdG含量增加、γ-H2AX蛋白表达增加以及DNA修复酶PARP-1的过度激活。镉暴露降低了NAD含量和SIRT1活性，增加了LC3 II、ATG5，特别是p62蛋白的表达。此外，镉诱导的氧化DNA损伤导致PARP-1过度激活、SIRT1活性降低和自噬通量阻滞，活性氧清除剂NAC的应用证明了这一点。用药物抑制剂PJ34抑制PARP-1激活可恢复NAD含量和SIRT1活性。用药物激活剂RSV激活SIRT1可逆转镉诱导的自噬通量阻滞和细胞损伤。体内数据表明，镉处理导致肾组织微观结构破坏，肌酐和尿素氮清除率降低，MDA含量升高，抗氧化剂（GSH、T-SOD、CAT和T-AOC）的活性或含量降低。镉处理导致氧化DNA损伤和PARP-1激活，NAD含量降低，SIRT1活性降低，自噬通量受损。值得注意的是，日粮中添加Lut可显著减轻镉诱导的鸡肾组织的这些改变。总之，日粮中添加Lut通过其强大的抗氧化特性，减轻了氧化DNA损伤激活的PARP-1介导的SIRT1活性降低，修复了自噬通量阻滞，从而减轻了镉诱导的鸡肾损伤。
