[Mechanisms of nephrotoxicity of novel anticancer compound maleimide derivative MI-1]

The features of the impact of the maleimide derivative 1-(4-Cl-benzyl)-3-chloro-4-(CF3-fenilamino)-1H-pyrrole-2,5-dione (MI-1) on the viability and apoptosis-induced cell death of renal proximal and distal tubular epithelial cells and the amount of total and phosphorylated ERK1/2 were studied in order to establish possible mechanisms of nephrotoxicity induced by of MI-1. The viability and apoptosis of renal epithelial tubular cells after incubation with MI-1 were perfomed by 3,4,5-dymetyltiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT)-test and by flow cytometry after staining with specific antibodies to annexin V, respectively. The amount of ERK 1/2 was determined by Western blotting. The data indicate that MI-1 was more toxic with respect to the epithelial cells of distal than proximal tubule cells. The apoptosis-induced cell death pathway is involved in the mechanisms of MI-1 cytotoxicity. One of the possible mechanisms of MI-1 nephrotoxicity is increase in phosphorylation of ERK1/2 in the distal tubules. At the same time the increase amount of total ERK1/2 in proximal tubules under the influence of MI-1 may contribute to the survival of proximal tubular epithelial cells under the impact of a toxic factor or oxidative stress.