Gentamicin is an
aminoglycoside antibiotic widely used against
infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy.
Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of
gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular
necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by
drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by
megalin and
cubulin, which transports
proteins and organic
cations inside the cells.
Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the
drug over an undetermined threshold destabilizes intracellular membranes and the
drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal
cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of
gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular
calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of
gentamicin, such as reduced renal blood flow and
inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death.