Stimulation of glomerular epithelial cell growth by doxorubicin

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.