Gekle M, Silbernagl S
Department of Physiology, University of Würzburg, Germany.
Kidney Blood Press Res. 1996;19(5):225-35. doi: 10.1159/000174080.
Ochratoxin A (OTA) is a secondary fungal metabolite that has been detected in a variety of animal chows, human food and in up to 80% of human blood samples of several Western countries. Its main target is the kidney. OTA is the causing agent of Danish porcine nephropathy and increases the incidence of renal carcinomas and adenomas in rats. Pathophysiological studies revealed that OTA acts on different sites along the nephron. Acute OTA exposure leads to an impairment of postproximal nephron function, predominantly of the collecting duct, resulting in altered electrolyte and titratable acid excretion. The underlying mechanism is most probably a blockade of anion conductance in the plasma membrane at nanomolar concentrations of OTA with subsequent disturbance of cellular acid-base homeostasis as shown in cultured kidney cells. Disturbance of cellular pH homeostasis is probably also involved in OTA-induced transformation of cultured kidney cells. Chronic OTA exposure leads to an additional reduction in the urine concentrating ability. Renal hemodynamics and the secretory function of the proximal tubule are affected by OTA after prolonged but not by acute exposure. OTA increases resistance in the vas efferens with a subsequent decrease in renal blood flow and glomerular filtration rate. Proximal tubular cells respond to OTA with a dramatic reduction in the secretory capacity for organic anions. The resorptive capacity for small molecules like amino acids is affected only to a minor extent, whereas endocytic uptake of albumin is clearly reduced. Furthermore, OTA has a mitogenic potential on rat proximal tubular cells in primary culture if applied in nanomolar concentrations but inhibits cell growth at micromolar concentrations. According to the above-described effects OTA exerts a complex action on renal function depending on the dose and time of exposure. The high incidence of OTA in human food and blood samples taken together with its diverse effects on renal function should attract further attention to this mycotoxin as a possible candidate for renal malfunction of unknown origin in humans.
赭曲霉毒素A（OTA）是一种真菌次生代谢产物，已在多种动物饲料、人类食物中被检测到，在一些西方国家高达80%的人类血液样本中也能发现它。它的主要靶器官是肾脏。OTA是丹麦猪肾病的致病因子，可增加大鼠肾癌和腺瘤的发病率。病理生理学研究表明，OTA作用于肾单位的不同部位。急性接触OTA会导致近端肾单位功能受损，主要是集合管功能受损，从而导致电解质和可滴定酸排泄改变。其潜在机制很可能是在纳摩尔浓度的OTA作用下，质膜上的阴离子电导被阻断，随后细胞酸碱平衡受到干扰，这在培养的肾细胞中已得到证实。细胞pH稳态的干扰可能也与OTA诱导培养的肾细胞转化有关。长期接触OTA会导致尿液浓缩能力进一步下降。长期而非急性接触OTA会影响肾脏血流动力学和近端小管的分泌功能。OTA会增加出球小动脉阻力，随后肾血流量和肾小球滤过率降低。近端小管细胞对OTA的反应是有机阴离子分泌能力显著下降。氨基酸等小分子的重吸收能力仅受到轻微影响，而白蛋白的内吞摄取明显减少。此外，在原代培养中，如果以纳摩尔浓度应用，OTA对大鼠近端小管细胞具有促有丝分裂潜力，但在微摩尔浓度下会抑制细胞生长。根据上述作用，OTA对肾功能的影响取决于接触剂量和时间，具有复杂性。OTA在人类食物和血液样本中的高发生率及其对肾功能的多种影响，应进一步引起人们对这种霉菌毒素的关注，它可能是人类不明原因肾功能障碍的一个潜在因素。
