Tian Yahui, Yang Yaohui, Gao Lei, Zhao Haijiao, Peng Xiaolan, Zhang Zhongwen, Wu Guojuan
Laboratory of Pharmacology of Chinese Veterinary Medicine, Department of Animal Science and Technology, College of Animal Science and Technology, Beijing University of Agriculture , Beijing , China.
Toxicol Mech Methods. 2014 Sep;24(6):377-84. doi: 10.3109/15376516.2014.920448. Epub 2014 Jun 27.
Aristolochic acid nephropathy (AAN) is mainly caused by aristolochic acid I (AAI), but the actual mechanism is still uncertain. The current study explored the correlation among the expression of Smad7, p300, histone deacetylase-1 (HDAC1) and the development of AAN using transmission electron microscopy (TEM), RT-PCR, and western blotting in the AAN mouse model and in the AAN cell model. TEM revealed that the renal tubular epithelial cells from the AAI-treated mice presented organelle damages and nuclear deformation. We found that a certain dose of AAI caused renal fibrosis and induced renal tubular epithelial cells to differentiate into myofibroblasts. There was a gradual increase in the expression of HDAC1 mRNA and protein observed using RT-PCR and western blotting in the AAN cell model compared with the control group. Gradual decrease in the expression of Smad7 and p300 mRNA and protein was revealed in the AAN mouse and cell models compared with the control group. These results suggest that AAI dose dependently contributed to the development of AAN, and HDAC1 and p300 participate in the modulation of TGF-β/Smad pathway-mediated renal interstitial fibrosis.
马兜铃酸肾病（AAN）主要由马兜铃酸I（AAI）引起，但其具体机制仍不明确。本研究采用透射电子显微镜（TEM）、逆转录-聚合酶链反应（RT-PCR）和蛋白质印迹法，在AAN小鼠模型和AAN细胞模型中探讨了Smad7、p300、组蛋白去乙酰化酶-1（HDAC1）的表达与AAN发展之间的相关性。TEM显示，经AAI处理的小鼠肾小管上皮细胞出现细胞器损伤和核变形。我们发现，一定剂量的AAI可导致肾纤维化，并诱导肾小管上皮细胞分化为肌成纤维细胞。与对照组相比，在AAN细胞模型中使用RT-PCR和蛋白质印迹法观察到HDAC1 mRNA和蛋白表达逐渐增加。与对照组相比，在AAN小鼠和细胞模型中发现Smad7和p300 mRNA及蛋白表达逐渐降低。这些结果表明，AAI剂量依赖性地促进了AAN的发展，且HDAC1和p300参与了转化生长因子-β/ Smad通路介导的肾间质纤维化的调控。
