Lebeau Catherine, Debelle Frédéric D, Arlt Volker M, Pozdzik Agnieszka, De Prez Eric G, Phillips David H, Deschodt-Lanckman Monique M, Vanherweghem Jean-Louis, Nortier Joëlle L
Laboratory for Research on Peptide Metabolism, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Nephrol Dial Transplant. 2005 Nov;20(11):2321-32. doi: 10.1093/ndt/gfi042. Epub 2005 Aug 2.
Aristolochic acid (AA), the plant extract of Aristolochia species, is involved in the onset of progressive tubulointerstitial renal fibrosis in humans. Clinical and in vitro findings have previously suggested that the proximal tubule was the target of AA.
Using a rat model of AA nephropathy, the proximal tubular lesions induced by daily subcutaneous injections of AA for 35 or 5 days were characterized biochemically and histologically. Urinary excretion of proteins, albumin, low molecular weight proteins, N-acetyl-beta-d-glucosaminidase, alpha-glutathione S-transferase, leucine aminopeptidase and neutral endopeptidase (NEP) was determined and related to histological conventional findings and immunostainings of NEP and megalin.
In both protocols, an acute phase of release of urinary markers was observed within the first 3 days of AA treatment in parallel with a significant increase of specific AA-related DNA adducts reflecting early tubular intoxication. A dramatic loss of the proximal tubule brush border was histologically confirmed, while the expression of megalin decreased at the damaged apical epithelium (mainly of the S3 segment).
Proximal tubule injury occurs early after AA intoxication in rats, with a link between specific AA-DNA adduct formation, decreased megalin expression and inhibition of receptor-mediated endocytosis of low molecular weight proteins, bringing in vivo confirmation of previous in vitro studies.
马兜铃酸（AA）是马兜铃属植物的提取物，与人类进行性肾小管间质肾纤维化的发病有关。临床和体外研究结果此前表明近端小管是AA的作用靶点。
采用AA肾病大鼠模型，对每日皮下注射AA 35天或5天所诱导的近端小管病变进行生化和组织学特征分析。测定尿蛋白、白蛋白、低分子量蛋白、N-乙酰-β-D-氨基葡萄糖苷酶、α-谷胱甘肽S-转移酶、亮氨酸氨肽酶和中性内肽酶（NEP）的排泄情况，并将其与组织学常规检查结果以及NEP和巨膜蛋白的免疫染色结果相关联。
在这两种方案中，AA治疗的前3天内均观察到尿标志物释放的急性期，同时反映早期肾小管中毒的特定AA相关DNA加合物显著增加。组织学证实近端小管刷状缘显著丧失，而巨膜蛋白在受损的顶端上皮（主要是S3段）表达下降。
大鼠AA中毒后早期即发生近端小管损伤，特定AA-DNA加合物形成、巨膜蛋白表达降低与低分子量蛋白受体介导的内吞作用受抑制之间存在关联，这为先前的体外研究提供了体内证据。
