STIMULATION OF GLOMERULAR EPITHELIAL-CELL GROWTH BY DOXORUBICIN

Although doxorubicin nephrosis is commonly used as a model of nephroti c syndrome in the rat, the mechanism of glomerular injury remains unkn own. Since a study by others using nonrenal cell lines showed that dox orubicin could increase cell growth at concentrations below the cytoto xic range, experiments were performed to determine whether doxorubicin had similar effects on glomerular cells. At low concentrations (appro ximate to 10(-10) to 10(-7) mol/L), doxorubicin causes a 1.5-fold to t hree-fold stimulation of primary culture and cloned, passaged glomerul ar epithelial cell (GEC) growth, as assessed by cell counting, incorpo ration of tritiated thymidine, and by a fluorescence assay of cell gro wth. 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. E xposure to low concentrations of doxorubicin increased GEC growth unde r low serum conditions after doxorubicin treatment. Conditions that pr omoted high rates of GEC proliferation before doxorubicin exposure (pr e-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-prom oting factors ; present in serum. These studies demonstrate that unlik e the growth-inhibiting effect of higher concentrations, the growth-pr omoting effect of low concentrations of doxorubicin is specific for GE Cs, the glomerular cell population that shows pathologic and functiona l evidence of injury in doxorubicin nephrosis in vivo. These findings, along with those of others, lead to the hypothesis that at higher con centrations, doxorubicin and other exogenous or endogenous growth-prom oting compounds may cause GEC injury by ''overstimulation'' of the sam e pathways that promote growth at lower concentrations.