Bertolatus J A
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City.
J Lab Clin Med. 1994 Dec;124(6):827-36.
Although doxorubicin nephrosis is commonly used as a model of nephrotic syndrome in the rat, the mechanism of glomerular injury remains unknown. Since a study by others using nonrenal cell lines showed that doxorubicin could increase cell growth at concentrations below the cytotoxic range, experiments were performed to determine whether doxorubicin had similar effects on glomerular cells. At low concentrations (approximately 10(-10) to 10(-7) mol/L), doxorubicin causes a 1.5-fold to three-fold stimulation of primary culture and cloned, passaged glomerular epithelial cell (GEC) growth, as assessed by cell counting, incorporation of tritiated thymidine, and by a fluorescence assay of cell growth. At these concentrations, doxorubicin had no effect on the growth rate of mesangial cells (MCs). Higher doxorubicin concentrations (> 10(-6) mol/L) inhibited the growth of GECs and MCs to a similar degree. Exposure to low concentrations of doxorubicin increased GEC growth under low serum conditions after doxorubicin treatment. Conditions that promoted high rates of GEC proliferation before doxorubicin exposure (pre-exposure to high serum concentrations, or use of subconfluent "stock" cultures) abrogated the growth response to doxorubicin, suggesting that doxorubicin stimulates GEC growth by substituting for growth-promoting factors present in serum. These studies demonstrate that unlike the growth-inhibiting effect of higher concentrations, the growth-promoting effect of low concentrations of doxorubicin is specific for GECs, the glomerular cell population that shows pathologic and functional evidence of injury in doxorubicin nephrosis in vivo. These findings, along with those of others, lead to the hypothesis that at higher concentrations, doxorubicin and other exogenous or endogenous growth-promoting compounds may cause GEC injury by "overstimulation" of the same pathways that promote growth at lower concentrations.
虽然阿霉素肾病通常被用作大鼠肾病综合征的模型，但其肾小球损伤机制仍不清楚。由于其他研究人员利用非肾细胞系进行的一项研究表明，阿霉素在低于细胞毒性范围的浓度下可促进细胞生长，因此进行了实验以确定阿霉素对肾小球细胞是否有类似作用。在低浓度（约10^(-10)至10^(-7)mol/L）下，通过细胞计数、氚标记胸腺嘧啶核苷掺入以及细胞生长荧光测定评估，阿霉素可使原代培养及克隆传代的肾小球上皮细胞（GEC）生长增加1.5倍至3倍。在这些浓度下，阿霉素对系膜细胞（MC）的生长速率无影响。更高的阿霉素浓度（>10^(-6)mol/L）对GEC和MC的生长有相似程度的抑制作用。阿霉素处理后，在低血清条件下暴露于低浓度阿霉素可增加GEC生长。在阿霉素暴露前促进GEC高增殖率的条件（预先暴露于高血清浓度，或使用亚汇合“储备”培养物）消除了对阿霉素的生长反应，提示阿霉素通过替代血清中存在的生长促进因子来刺激GEC生长。这些研究表明，与高浓度时的生长抑制作用不同，低浓度阿霉素的生长促进作用对GEC具有特异性，GEC是在体内阿霉素肾病中显示损伤病理和功能证据的肾小球细胞群体。这些发现以及其他研究结果导致这样一种假说，即高浓度时，阿霉素和其他外源性或内源性生长促进化合物可能通过“过度刺激”在低浓度时促进生长的相同途径而导致GEC损伤。
