Megalin Deficiency Offers Protection from Renal Aminoglycoside Accumulation

Abstract

Aminoglycosides are antibiotics commonly used to treat life-threatening Gram-negative bacterial infections. However, their use is hampered by their severe nephrotoxicity due to accumulation in renal proximal tubules. Several pathways have been implicated in the renal uptake of aminoglycosides including megalin, an endocytic receptor in proximal tubular cells. Here, we have used mouse models with genetic or functional megalin deficiency to explore the contribution of megalin and other pathways to renal aminoglycoside uptake in vivo. We demonstrate that the uptake of aminoglycosides into the kidney directly correlates with renal megalin activity and is completely eliminated in mice lacking the receptor. Thus, our studies provide unequivocal evidence that megalin is the only major pathway responsible for renal aminoglycoside accumulation and that the receptor represents a unique drug target to prevent aminoglycoside-induced nephrotoxicity in patients.

Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines

“…Some of our observed cytotoxic and cytostatic effects of clindamycin, macrolides, fluoroquinolones, linezolid, chloramphenicol, rifampin, and tetracycline on PHO can be explained by an impairment of mitochondrial energetics, whereas the inhibitors of the bacterial cell wall syntheses (with the exception of cefazolin with an unknown eukaryotic target [16]) and aminoglycosides displayed no effect on PHO because of ab- sence of a specific target or because they could not enter the cells in the absence of a specific receptor (34,43). In contrast, chloramphenicol and linezolid increased the lactate production comparable to the specific inhibitors of the respiratory chain presumably by inhibition of mitochondrial protein synthesis, which was actually shown in vitro for chloramphenicol (30,39).…”

Experimental gentamicin-induced nephrotoxicity in the sheep

“…In megalin-deficient mice, lack of this uptake pathway results in tubular resorption deficiency and low molecular weight proteinuria (20). Other effects of gentamicin such as phospholipidosis, oxidative stress, extracellular calcium sensing receptor stimulation, and energetic catastrophe have been also connected with cell death.…”

“…Gentamicin was first isolated from Micromonospora purpurea, gram-positive bacteria widely present in water and soil (3). Because of its effectiveness and the low rate of bacterial resistance, GM is often considered as a drug of choice to treat life-threatening infections such as sepsis (15,20). It acts by irreversibly binding the 30S subunit of the bacterial ribosome, causing misreading of t-RNA, leaving the bacterium unable to synthesise proteins vital to its growth (3).…”

Poly-l-aspartic Acid Enhances and Prolongs Gentamicin-mediated Suppression of the CFTR-G542X Mutation in a Cystic Fibrosis Mouse Model

“…Aminoglycoside uptake into mammalian cells is mediated primarily by megalin, a multi-ligand endocytic receptor that is particularly abundant in the proximal tubules of the kidney and the hair cells of the inner ear (27,28). It has been estimated that 90% of internalized aminoglycosides accumulate within the lysosome, where they induce lysosomal phospholipidosis by inhibiting the activity of phospholipases in the lysosomal membrane (29 -31).…”