An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin.
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.
Quiros
Yaremi
Y
Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain.
Vicente-Vicente
Laura
L
Morales
Ana I
AI
López-Novoa
José M
JM
López-Hernández
Francisco J
FJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D005839:Gentamicins / Q000633:toxicity*; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects*; D010743:Phospholipids / Q000378:metabolism; D011489:Protein Denaturation; D013347:Subcellular Fractions / Q000187:drug effects
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010743:Phospholipids