Aminoglycosides endocytosis

Figure 29.10. Postulated pathways of aminoglycoside-induced cellular injury. On the left, aminoglycoside (AG) enters the cell by pinocytosis and endocytosis, subsequently fusing with a primary lysosome (L). Aminoglycosides may interfere with normal lysosomal function, forming myeloid bodies (center). Additionally, aminoglycosides may destabilize lysosomes, leading to release of intralysosomal enzymes (lower left). Intracellular aminoglycosides may produce direct injury to intracellular organelles such as mitochondria. (Adapted from G.J. Kaloyanides and E. Pastoriza-Munoz, Kidney Int. 18, 571-582,1980.)...

One of the mechanisms of active reabsorption is endocytosis. Fluid phase endocytosis consists of the incorporation of fluid and solutes in vesicles formed at the base of the brush border membrane of the proximal tubular cells (Figure 1). A more efficient absorptive endocytosis involves first binding of a drug, such as the cationic aminoglycoside and/or may be cadmium [30, 31], to a carrier (phosphatidyhnositol) located in the luminal membrane of the wall of the pinocytotic vesicle occurs followed by endocytosis and lysosomal fusion [32, 33]. 

Gentamicin is more toxic to LLC-PKj monolayers when exposed at the apical side, indicating a preferential uptake from the luminal membrane [136]. The uptake mechanism is proposed to be via megalin mediated endocytosis, a protein which is abundantly expressed in the proximal tubule [137]. A pathway delineated in LLC-PKl cells is proposed, whereby internalized aminoglycosides and other small molecular weight cationic compounds are transported from the early and late endosomes, through the Golgi complex. 

After the initial binding to the anionic phospholipids of the PTC, the aminoglycoside molecule is quickly transferred to the transmembrane protein megalin and endocytosed [42, 43, 48-50, 52-59, 66-68, 72, 73]. Aminoglycosides enter the PTC on either the apical or basolateral plasma membrane via receptor-mediated endocytosis. and are ultimately sequestered in the same endosomal compartment [68]. In an experiment with LLC-PKl cells. Ford et al. demonstrated that aminoglycosides were internalized equally across the apical and basolateral membranes by receptor-mediated endocytosis. This was followed by colocalization within the lysosomal compartment and similar magnitudes of cellular dysfunction [68]. 

Aminoglycosides exemplify compounds that enter the proximal tubular cells by endocytosis and then are stored in secondary lysosomes, which have a lamellate... 

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