Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists

Watanabe, Asako; Nagai, Junya; Adachi, Yoshinori; Katsube, Takayuki; Kitahara, Yasumi; Murakami, Teruo; Takano, Mikihisa

doi:10.1016/j.jconrel.2003.12.005

Cited by 64 publications

(59 citation statements)

References 30 publications

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“…In accordance with this, megalin knock-out mice are protected from the renal accumulation of AGs [12]. Furthermore, protein and peptide ligands which compete with AGs for binding to megalin are effective in reducing AG accumulation in cell lines expressing megalin and the appearance of urinary biomarkers of AG-induced tubular damage in vivo [13].…”

Section: Introductionsupporting

confidence: 53%

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

Antoine¹,

Srivastava²,

Pirmohamed³

et al. 2010

Biochemical Pharmacology

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International audienceNephrotoxicity due to renal proximal tubule accumulation of aminoglycoside (AG) antibiotics, such as gentamicin, represents a major clinical problem. Receptor-mediated endocytosis via the multi-ligand receptor megalin is thought to be a key mechanism in the cellular uptake of AGs and nephrotoxicity. This process can be modulated by the intracellular concentration of isoprenoid pyrophosphates derived from the processing of mevalonate by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Post-translation modifications by isoprenoid pyrophosphates are necessary for GTP-binding protein function. Given that statins inhibit HMG-CoA reductase and therefore affect the concentration of isoprenoid pyrophosphates, we have tested the hypothesis that statins will lead to a reduction in AG renal proximal tubule accumulation and cytotoxicity. Gentamicin accumulated within cultured proximal tubule derived opossum kidney (OK) cells and led to dose- and time-dependent cell death which was inhibited by non-toxic doses of simvastatin (IC 1.3μM), rosuvastatin (IC 16.3μM) and pravastatin (IC 38.8μM). The mechanism of inhibition was linked to the degree of cholesterol synthesis inhibition and GTP-binding protein unprenylation. Moreover, co-incubation with mevalonate or geranyl-geranyl pyrophosphate, products of HMG-CoA reductase, reversed the inhibitory effect of statins on cellular accumulation and cytotoxicity of gentamicin. In summary, our data suggest that the inhibition of the mevalonate pathway by statins may provide a potential therapeutic strategy to prevent AG-induced nephrotoxicity

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Section: Introductionsupporting

confidence: 53%

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

Antoine¹,

Srivastava²,

Pirmohamed³

et al. 2010

Biochemical Pharmacology

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“…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). This strategy may be useful in preventing drug accumulation in the fetal kidney during intrapartum AG administration but only if placental drug transport remains unaltered by megalin receptor blockade.…”

Section: Introductionmentioning

confidence: 99%

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

Akour

Kennedy

Gerk

2015

AAPS J

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Abstract. Aminoglycosides (AG) are known to readily cross the placenta, although the mechanisms responsible for placental transport have not been characterized. Megalin is expressed in human placenta, and it is reasonable to speculate, given its role in renal AG uptake, that it is similarly involved in placental transport. However, the role of megalin in placental AG uptake has not been established. An in vitro model to study megalin-mediated placental transport has also not been previously described. The objectives of this study, therefore, were to evaluate the human choriocarcinoma (BeWo) cell line as a model to study megalin-mediated placental transport and to assess the uptake kinetics of gentamicin, an AG antibiotic, using this in vitro model. BeWo cells were grown on Transwell® plates, and megalin expression and functional activity were assessed. Uptake of 3 H-gentamicin was also evaluated in the presence and absence of megalin inhibitors. Expression of megalin protein and mRNA in BeWo cells were confirmed via immunoblot and qPCR analysis. Uptake of fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) (a megalin substrate) was time-, concentration-, and temperature-dependent consistent with a transporter-mediated process. FITC-BSA uptake was also significantly reduced in the presence of unlabeled gentamicin (a megalin substrate) and sodium maleate (to induce megalin shedding) suggesting that megalin is functionally active in BeWo cells. Gentamicin uptake exhibited time and temperature dependence, saturability and Michaelis-Menten kinetics, all of which suggest a transporter-mediated process. Gentamicin uptake was also significantly reduced in the presence of the megalin inhibitors RAP and EDTA suggesting that megalin is likely involved in gentamicin uptake.

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“…ROS produce cellular injury and necrosis via several mechanisms, including peroxidation of membrane lipids, protein denaturation, and DNA damage (8). Renal accumulation of gentamicin and lysosomal phospholipidosis disrupts normal renal function and is implicated in the induction of nephrotoxicity (9,10).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Nephroprotective Effects of Hydroalcoholic Extract of Cyperus scariosus Linn. in Gentamicin-induced Acute Kidney Injury in Wistar Albino Rats

Gajjar

Aiwale

Anovadiya

et al. 2016

Jundishapur J Nat Pharm Prod

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Background: Gentamicin is a commonly used antibiotic for the treatment of Gram-negative infections, but nephrotoxicity limits its use. Cyperus scariosus Linn. (CS) has been found to have antioxidant properties in vitro. Objectives: The aim of this study was to evaluate the nephroprotective effects of CS in gentamicin-induced acute kidney injury (AKI). Methods: The animals were divided into nine groups. AKI was produced with a 100 mg/kg intraperitoneal (i.p.) injection of gen-

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Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists

Cited by 64 publications

References 30 publications

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

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

Evaluation of Nephroprotective Effects of Hydroalcoholic Extract of Cyperus scariosus Linn. in Gentamicin-induced Acute Kidney Injury in Wistar Albino Rats

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