Protective effect of three xanthine derivatives (theophylline, caffeine and pentoxifylline) against the cyclosporin A-induced glomerular contraction in isolated glomeruli and cultured mesangial cells.

Cyclosporin A (CyA), an immunosuppressive agent, induces in vivo a severe nephrotoxicity with large decrease in renal hemodynamics correlated with in vitro glomerular contraction. The aim of this study is to show the ability of three xanthine derivatives, caffeine, theophylline and pentoxifylline, to diminish the CyA-induced in vitro glomerular contraction. The use of isolated glomeruli and cultured rat mesangial cells permits us to evaluate by quantitative and qualitative morphometric analysis the contraction elicited either with CyA alone or with previous treatment with nontoxic concentrations of xanthine derivatives. Indirect immunofluorescence of actin filaments makes it possible to appreciate qualitative morphometric changes in mesangial cells. A 10-min pretreatment with caffeine, theophylline or pentoxifylline (10(-4) to 10(-9) M) abolishes the contraction elicited with 10(-6) M CyA. CyA alone induces -13.9% compared to CyA with 10(-6) M pentoxifylline which induces only -3.2% of reduction of planar glomerulus surface area after 30 min. Similar results were provided with cultured rat mesangial cells. As shown by indirect immunofluorescence xanthine derivatives prevent the cytoskeletal reorganization (alpha-actin) of cultured mesangial cells which occurs with CyA. The marked constriction induced by CyA in isolated glomeruli and mesangial cells can be prevented by xanthine derivatives.