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Megalin deficiency offers protection from renal aminoglycoside accumulation
Christian Schmitz1, Jan Hilpert, Christian Jacobsen
1Max-Delbrueck-Center for Molecular Medicine, Berlin D-13125, Germany.
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.
Insights
Aminoglycoside antibiotics cause kidney damage by accumulating in renal tubules. Megalin, a receptor, is the primary pathway for this uptake, offering a target to prevent toxicity.
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Aminoglycosides are vital antibiotics for Gram-negative infections.
- Nephrotoxicity limits aminoglycoside use due to renal proximal tubule accumulation.
- Megalin, an endocytic receptor, is a suspected pathway for renal aminoglycoside uptake.
Purpose of the Study:
- To investigate the role of megalin in renal aminoglycoside uptake in vivo.
- To determine if megalin is the sole major pathway for aminoglycoside accumulation in kidneys.
Main Methods:
- Utilized mouse models with genetic and functional megalin deficiency.
- Assessed renal aminoglycoside uptake in megalin-deficient and control mice.
Main Results:
- Renal aminoglycoside uptake directly correlated with megalin activity.
- Aminoglycoside uptake was completely abolished in mice lacking megalin.
- Established megalin as the exclusive major pathway for renal aminoglycoside accumulation.
Conclusions:
- Megalin is unequivocally the primary determinant of renal aminoglycoside uptake.
- Megalin presents a specific therapeutic target for mitigating aminoglycoside-induced nephrotoxicity.