Induction of endothelin in rat kidney after cyclosporine A treatment

In the present study, we investigated the variation of endothelin (ET) levels in various organs (kidney, liver, spleen and heart) of rats after 7 and 15 days of Cyclosporine A (CsA) treatment. Moreover, we studied whether these modifications are related to major toxic effects, known to be a complication of CsA treatment (i. e. nephrotoxicity). The morphology of liver, spleen and heart in rats treated with CsA for 7 and 15 days was similar to that in control rats. The amounts of ET protein as determined by Western blot analysis were very low in all organs. However, we found lesions in kidneys of rats treated with CsA for 15 days but not in kidneys of rats treated for 7 days. Immunohistochemical analysis using an ET polyclonal antibody revealed that proximal tubules of animals treated for 15 days were strongly ET positive whereas distal tubules and glomerula showed only weak positivity as those in control rats. Western blot analysis revealed an increase in ET protein in treated rats. On the basis of these data, we conclude that CsA induced evident nephrotoxicity already after 15 days of treatment and that toxic effects of CsA were related to the amounts of ET found. An explanation for these findings is that ET, produced by epithelial cells, is filtered through the glomerular tuft and resorbed by tubular epithelial cells. Since variation in levels of ET was visible only in proximal tubules, we conclude that CsA treatment during a brief period produced side effects that can be considered as acute toxicity. Our finding may help to understand the mechanism of CsA toxicity and may provide important clues for pharmacological strategies to reduce CsA toxicity.