马兜铃酸肾毒性的临床特征、分子机制及治疗策略

摘要

不同于马兜铃酸(Aristolochic acid,AA)突变指纹诱发肝癌,AA具有明确的肾毒性,并且会诱发3种不同类型的马兜铃酸肾病(Aristolochic acid nephropathy,AAN).AA肾毒性的临床特征为缺乏特异性症状、少量肾小管性尿蛋白、进行性肾功能衰竭、贫血以及广泛的寡细胞性肾间质纤维化伴肾小管萎缩.AA肾毒性的分子机制主要是指AA通过影响微小RNA、内质网应激、氧化应激而直接或间接地诱导肾脏细胞凋亡;此外,肾组织炎症可能也可能是AA肾毒性的分子机制之一.AA肾毒性的治疗策略包括低剂量糖皮质激素、前列腺素E1、骨髓间充质干细胞以及中药复方及其提取物等.近年来,我国对含AA的中药材和中成药实施了严格管制,使得AA肾毒性事件和AAN发生率逐年减少.尽管如此,中药相关的药物性肾损伤(Drug-induced kidney injury,DKI)还是不容忽略的问题,其中,建立中药肾毒性的评价方法是认识其分子机制、探寻其治疗策略的关键所在.%It is reported that aristolochic acid(AA)not only has the definite nephrotoxicity but also causes the 3 different types of aristolochic acid nephropathy(AAN),which is different from the mutational signature of AA in inducing hepatocellular carcinomas.The clinical features of AA-induced nephrotoxicity include the lack of specific symptoms,a small amount of tubular proteinuria,the progressive renal failure,anemia and the extensive renal interstitial fibrosis with few infiltrated cells,along with tubular atrophy.The molecular mechanisms of AA-indueed nephrotoxicity mainly refer to the induction of renal cellular apoptosis by affecting microRNAs(miRNAs),endoplasmic reticulum stress and oxidative stress directlyor indirectly.In addition,renal inflammation is probably related to the molecular mechanism of AA-induced nephrotoxicity.The therapeutic strategies of AA-induced nephrotoxicity contain the low-dosage of glucocorticoids,prostaglandin E1,bone marrow mesenchymal stem cells and Chinese herbal compound prescriptions and their extracts.Recently Chinese government has maintained strict controls on Chinese medicinal materials and Chinese traditional patent medicines containing AA,so that the incidences of AA-induced nephrotoxicity and AAN have been decreasing year by year.Nevertheless,Chinese herbal medicines (CHM) related drug-induced kidney injury(DKI)cannot be ignored,in which,establishing the evaluation methods of nephrotoxicity of CHM is the key point to understand the molecular mechanisms and explore the therapeutic strategies.