Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation
Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation
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DOI：
10.1038/sj.ki.5002714
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发表时间：
2008-03-01
影响因子：
19.6
通讯作者：
Nortier, J. L.
中科院分区：
文献类型：
--
作者：
Pozdzik, A. A.;Salmon, I. J.;Nortier, J. L.
草药中的马兜铃酸污染会导致人类间质纤维化、小管萎缩和肾功能衰竭。为了研究这种肾脏疾病的病理生理机制，我们研究了用马兜铃酸治疗的Wistar大鼠，并测量了小管和间质细胞增殖、上皮/间充质细胞标志物表达、小管膜完整性、肌成纤维细胞积累、氧化应激、线粒体损伤、小管凋亡和纤维化。在给药后5天内，明显出现氧化应激、钙粘蛋白缺失伴静脉蛋白表达、基底膜脱落伴caspase-3活性表达以及小管细胞线粒体损伤。在慢性期，间质间充质细胞在胶原沉积区聚集。近端小管细胞再生和凋亡受损导致小管萎缩，几乎没有去分化细胞跨膜迁移。我们认为，在马兜铃酸中毒时，常驻成纤维细胞的激活在肾纤维化过程中起着关键作用。
Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.