Abstract：
Balkan endemic nephropathy (BEN) is a chronic kidney disease that predominantly affects inhabitants of rural farming communities along the Danube River tributaries in the Balkans. Long-standing research has identified dietary exposure to aristolochic acids (AAs) as the principal toxicological cause. This study investigates the pathophysiological role of anemia in BEN, noting its earlier and more severe manifestation in BEN patients compared to those with other chronic kidney diseases. Utilizing a mouse model, our research demonstrates that prolonged exposure to aristolochic acid I (AA-I) (the most prevalent AA variant) leads to significant red blood cell depletion through DNA damage, such as DNA adduct formation in bone marrow, prior to observable kidney function decline. Furthermore, in vitro experiments with kidney cells exposed to lowered oxygen and pH conditions mimicking an anemia environment show enhanced DNA adduct formation, suggesting increased AA-I mutagenicity and carcinogenicity. These findings indicate for the first time a positive feedback mechanism of AA-induced anemia, DNA damage, and kidney impairment in BEN progression. These results not only advance our understanding of the underlying mechanisms of BEN but also highlight anemia as a potential target for early BEN diagnosis and therapy.
摘要：
巴尔干地方性肾病（BEN）是一种慢性肾脏疾病，主要影响巴尔干地区多瑙河支流沿线农村农业社区的居民。长期的研究已经确定饮食中接触马兜铃酸（AAs）是主要的毒理学原因。这项研究调查了贫血在BEN中的病理生理作用，注意到与其他慢性肾脏疾病患者相比，其在BEN患者中的表现更早，更严重。利用鼠标模型，我们的研究表明，长期暴露于马兜铃酸I（AA-I）（最普遍的AA变体）导致显著的红细胞消耗通过DNA损伤，比如骨髓中DNA加合物的形成，在可观察到的肾功能下降之前。此外，在体外实验中，肾细胞暴露于较低的氧气和pH条件下，模拟贫血环境显示出增强的DNA加合物形成，提示AA-I致突变性和致癌性增加。这些发现首次表明AA诱导贫血的正反馈机制，DNA损伤,和BEN进展中的肾脏损害。这些结果不仅促进了我们对BEN潜在机制的理解，而且还强调了贫血是早期BEN诊断和治疗的潜在目标。
