Mise en évidence et étude de l'apoptose induite par les antibiotiques du groupe des aminoglycosides
(2000)
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- Aminoglycoside antibiotics are nephrotoxic in clinics but cause acute tubular necrosis in experimental animals only when administered at supratherapeutic doses. In this study, we examined whether aminoglycosides would induce apoptosis in proximal tubules of rats treated with therapeutically-relevant dosages. We have demonstrated that aminoglycosides induce a large, dose- and time-dependent wave of apoptosis in proximal tubule epithelium. Apoptosis develops in parallel with the lysosomial phospholipidosis, and is accompanied by a process of cellular proliferation (nephrogenic repair). Tubular necrosis was only seen at high doses of gentamicin. <BR> comparative studies using different aminoglucosides have demonstrared a ranking gentamicin > netilmicin > amikacin = isepamicin, which is essentially the same that we and others have found regarding the nephrotoxic potential if these drgus. Comparison of the different aminoglycosides revealed for gentamicin, amikacin and isepamicin, a parallelism between the decree of the lysosomial phospholipidosis, the occurrence of apoptosis and the proliferative response indicative of tubular damage (gentamicin >> amikacin = isepamicin). By contrast, netilmicin induced a marked phospholipidoses with moderate apoptosis and proliferative response. <BR> Aminoglycoside-induced apoptosis has been reproduced in cultured cells incubated with these drugs (fibroblasts and two lines of renal cells). Like what is observed in vivo, apoptosis appears in cultured cells in parallel with the development of the aminoglycoside-induced phospholipidosis. Both apoptosis and phospholipidosis are considerable reduced in cells co-incubated with poly-aspartic acid, a polymer which has been shown to prevent aminoglycoside interaction with cell phospholipids. In rat fibroblast and MDCK cells, but not in LLC-PK1 cells, apoptosis due to gentamicin is decreased by cycloheximide, suggesting that de novo protein synthesis is a prerequisite to cell death. The involvement of caspases in the apoptotic process was investigated in MDCK cells exposed to gentamicin. As revealed by a fluorimetric assay, apoptosis is accompanied with an increase if caspases activity. DNA cleavage associated with apoptosis is inhibited by the caspase inhibitor Z-VAD.fmk, without evidence of a shift from apoptosis to necrosis. In MDCK and LLC-PK1 sublines selected after transfection with a bcl-2-carrying recombinants vector, Bcl-2 overexpression confers protection against gentamicin-induced apoptosis, with no effect on the phospholipidosis. Thus, apoptosis caused by aminoglycosides is not directly related to the phospholipidosis, but must probably involves Bcl-2 and/or its relatives
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El Mouedden, M. (2000). Mise en évidence et étude de l’apoptose induite par les antibiotiques du groupe des aminoglycosides. https://hdl.handle.net/2078.5/111090