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Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency

Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nep...

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Autores principales: Jado, Juan Carlos, Humanes, Blanca, González-Nicolás, María Ángeles, Camaño, Sonia, Lara, José Manuel, López, Beatriz, Cercenado, Emilia, García-Bordas, Julio, Tejedor, Alberto, Lázaro, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555100/
https://www.ncbi.nlm.nih.gov/pubmed/32899204
http://dx.doi.org/10.3390/antiox9090821
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author Jado, Juan Carlos
Humanes, Blanca
González-Nicolás, María Ángeles
Camaño, Sonia
Lara, José Manuel
López, Beatriz
Cercenado, Emilia
García-Bordas, Julio
Tejedor, Alberto
Lázaro, Alberto
author_facet Jado, Juan Carlos
Humanes, Blanca
González-Nicolás, María Ángeles
Camaño, Sonia
Lara, José Manuel
López, Beatriz
Cercenado, Emilia
García-Bordas, Julio
Tejedor, Alberto
Lázaro, Alberto
author_sort Jado, Juan Carlos
collection PubMed
description Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with gentamicin and/or cilastatin. In vivo nephrotoxicity was analyzed by measuring biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels. Megalin, mainly responsible for the entry of gentamicin into the cells, was also analyzed. Results show that cilastatin protects cells from gentamicin-induced AKI. Cilastatin decreased creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by gentamicin in rats. The interference of cilastatin with lipid rafts cycling leads to decreased expression of megalin, and therefore gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover, cilastatin did not prevent bacterial death by gentamicin. Cilastatin reduced gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of megalin-gentamicin endocytosis. Therefore, cilastatin might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced AKI in the clinical setting.
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spelling pubmed-75551002020-10-14 Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency Jado, Juan Carlos Humanes, Blanca González-Nicolás, María Ángeles Camaño, Sonia Lara, José Manuel López, Beatriz Cercenado, Emilia García-Bordas, Julio Tejedor, Alberto Lázaro, Alberto Antioxidants (Basel) Article Gentamicin is a used antibiotic that causes nephrotoxicity in 10–20% of treatment periods, which limits its use considerably. Our results have shown that cilastatin may be a promising therapeutic alternative in toxin-induced acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with gentamicin and/or cilastatin. In vivo nephrotoxicity was analyzed by measuring biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels. Megalin, mainly responsible for the entry of gentamicin into the cells, was also analyzed. Results show that cilastatin protects cells from gentamicin-induced AKI. Cilastatin decreased creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by gentamicin in rats. The interference of cilastatin with lipid rafts cycling leads to decreased expression of megalin, and therefore gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover, cilastatin did not prevent bacterial death by gentamicin. Cilastatin reduced gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of megalin-gentamicin endocytosis. Therefore, cilastatin might represent a novel therapeutic tool in the prevention and treatment of gentamicin-induced AKI in the clinical setting. MDPI 2020-09-03 /pmc/articles/PMC7555100/ /pubmed/32899204 http://dx.doi.org/10.3390/antiox9090821 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jado, Juan Carlos
Humanes, Blanca
González-Nicolás, María Ángeles
Camaño, Sonia
Lara, José Manuel
López, Beatriz
Cercenado, Emilia
García-Bordas, Julio
Tejedor, Alberto
Lázaro, Alberto
Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title_full Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title_fullStr Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title_full_unstemmed Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title_short Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency
title_sort nephroprotective effect of cilastatin against gentamicin-induced renal injury in vitro and in vivo without altering its bactericidal efficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555100/
https://www.ncbi.nlm.nih.gov/pubmed/32899204
http://dx.doi.org/10.3390/antiox9090821
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