Screening of the chemopreventive componds against aristolochic acid-induced nephropathy from natural products

• Main Authors: Yu-Ju Ding, 丁玉如
• Other Authors: Yau-Hung Chen
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/56600529645286014673

碩士 === 淡江大學 === 生命科學研究所碩士班 === 98 === Aristolochic acid (AA) occurs naturally in Aristolochiaceae plants, and toxicological studies have shown the role of AA in human aristolochic acid nephropathy (AAN). Most studies have focused on the adult toxicity of AA, but the embryonic toxicity and toxicological mechanisms are still not clear. Therefore, we used zebrafish embryos to investigate the effects of AA on embryonic development and toxicity. After 24-hpf embryos were treated with AA (10 ppm) for 7 hours, the 48-hpf embryo kidney (glomeruli, pronephric tubules, and pronephric ducts) and heart (deformed heart, swollen pericardial cavity,and hemorrhagic yolk sac) were severely damaged, and the 72-hpf survival rate was decreased to 14.2%. The glomerular filtration rate (GFR) of embryos was further examined after AA treatment. The GFR of embryos after 3-h AA treatment decreased to 71.5 ± 18.8%, while that after 5-h AA treatment decreased to 39.4 ± 15.9%. Taken together, AA caused renal injury and dysfunction, as well as reduced survival rate of zebrafish embryos. Besides, AA-induced apoptosis was observed. A significant decrease in the amount of erythrocytes and leukocytes was observed in AA-treated embryos. Moreover, erythrocytes became stationary in blood flow and even accumulated in renal tubules and intestinal tract. Based on quantitative PCR, mRNA expression of inflammatory genes (TNF-α, cox2, and mpo) was upregulated in AA-treated embryos. 12-h treatment (12-24 hpf) of resveratrol or ursolic acid before AA treatment (24-31 hpf) was found to inhibit AA-induced inflammation and attenuate but not completely reverse AA-induced renal injury. In summary, the cellular and molecular mechanisms of AA toxicity may result in inflammatory renal injury and hematopoietic dysfunction, severe defects of heart and kidney, and ultimately lead to kidney dysfunction and failure.