Role of megalin in renal handling of aminoglycosides

Abstract

The role of megalin in tissue distribution of aminoglycosides was examined in normal rats and maleate-treated rats that shed megalin from the renal brush-border membrane. In normal rats, amikacin administered intravenously accumulated most abundantly in the renal cortex, followed by the renal medulla. No amikacin was detected in other tissues. Tissue distributions of amikacin were well correlated with megalin levels in each tissue. Bolus administration of gentamicin increased urinary excretion of megalin ligands (vitamin D binding protein and calcium), suggesting the competition between gentamicin and these megalin ligands in renal tubules. Ligand blotting showed that binding of (45)Ca(2+) to megalin was inhibited by aminoglycosides. Both megalin levels and amikacin accumulation in renal cortex were decreased by maleate injection. Then, amikacin accumulation recovered proportionate to megalin levels. These findings suggest that megalin is involved in the renal cortical accumulation of aminoglycosides in vivo. In addition, the interaction between aminoglycosides and calcium in the kidney may be due to the competition among these compounds to bind to megalin.

Megalin Deficiency Offers Protection from Renal Aminoglycoside Accumulation

“…Previous studies on the role of megalin in renal aminoglycoside accumulation focused on the rat as a model system (11,19). Megalin antagonists were used to interfere with the activity of receptor and to test the consequences for aminoglycoside uptake in vivo.…”

“…This substance causes shedding of megalin from the brush-border surface, thus impairing receptor-mediated ligand uptake. In maleate-treated animals, the tubular clearance of aminoglycosides was decreased to the same extent as that of megalin ligands, suggesting uptake via the same receptor pathway (19).…”

“…Inhibition of megalin reduced the clearance of gentamicin by ϳ20% (11). Nagai et al (19) analyzed the aminoglycoside clearance in rats treated with maleate. This substance causes shedding of megalin from the brush-border surface, thus impairing receptor-mediated ligand uptake.…”

Intracellular pharmacodynamics of antibiotics

“…Cells displaying surface binding sites, such as kidney proximal tubular cells in vivo, however, accumulate aminoglycosides quite fast and extensively [50,51]. These sites have been identified as megalin (a protein binding polybasic compounds; [52][53][54]) on the one hand, and acidic phospholipids on the other hand [55].…”

The Role of Megalin in the Transport of Gentamicin Across BeWo Cells, an In Vitro Model of the Human Placenta

“…Megalin is responsible for the uptake of AGs into renal proximal tubular epithelial cells, the physiologic site of AG induced renal injury (10). Pharmacologic blockade of the megalin receptor has been shown to limit renal accumulation of AGs and prevent nephrotoxicity in animal models (11).…”