LEUPEPTIN AND E-64, INHIBITORS OF CYSTEINE PROTEINASES, PREVENT GENTAMICIN-INDUCED LYSOSOMAL PHOSPHOLIPIDOSIS IN CULTURED RAT FIBROBLASTS

Aminoglycoside antibiotics, such as gentamicin, cause an early lysosom al phospholipidosis in the renal cortex, which is considered as a key event in the onset of acute tubular necrosis induced by these drugs. I n a model of primary cultures of embryonic rat fibroblasts which devel op typical lysosomal phospholipidosis when incubated with gentamicin ( decrease of sphingomyelinase activity; increase in total cells lipid p hosphorus; appearance of so-called 'myeloid bodies' in lysosomes), we observed a protective effect exerted by inhibitors of cysteine protein ases (leupeptin, E-64) against this alteration on the basis of both bi ochemical and morphological criteria. Actually leupeptin and E-64 caus ed a marked stimulation of sphingomyelinase activity both in control a nd in gentamicin-treated cells, which we suggest to be the cause of pr otection.