Potentiation by nitric oxide of cyclosporin A and FK506-induced apoptosis in renal proximal tubule cells.
Proximal tubular epithelial cells (PTEC) exhibit a high sensitivity to undergo apoptosis in response to proinflammatory stimuli and immunosuppressors and participate in the onset of several renal diseases. This study examined the expression of inducible nitric oxide (NO) synthase after challenge of PTEC with bacterial cell wall molecules and inflammatory cytokines and analyzed the pathways that lead to apoptosis in these cells by measuring changes in the mitochondrial transmembrane potential and caspase activation. The data show that the apoptotic effects of proinflammatory stimuli mainly were due to the expression of inducible NO synthase. Cyclosporin A and FK506 inhibited partially NO synthesis. However, both NO and immunosuppressors induced apoptosis, probably through a common mechanism that involved the irreversible opening of the mitochondrial permeability transition pore. Activation of caspases 3 and 7 was observed in cells treated with high doses of NO and with moderate concentrations of immunosuppressors. The conclusion is that the cooperation between NO and immunosuppressors that induce apoptosis in PTEC might contribute to the renal toxicity observed in the course of immunosuppressive therapy.
Hortelano
Sonsoles
S
Institute of Biochemistry (CSIC-UCM), Faculty of Pharmacy, Complutense University, Madrid, Spain.
Castilla
Manuela
M
Experimental Medicine and Surgery Unit, Gregorio Marañón University General Hospital, Madrid, Spain.
Torres
Ana M
AM
Experimental Medicine and Surgery Unit, Gregorio Marañón University General Hospital, Madrid, Spain.
Tejedor
Alberto
A
Experimental Medicine and Surgery Unit, Gregorio Marañón University General Hospital, Madrid, Spain.
Boscá
Lisardo
L
Institute of Biochemistry (CSIC-UCM), Faculty of Pharmacy, Complutense University, Madrid, Spain.
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008074:Lipoproteins / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D008074:Lipoproteins; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D016559:Tacrolimus