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Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy

Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable...

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Autores principales: Opazo-Ríos, Lucas, Plaza, Anita, Sánchez Matus, Yenniffer, Bernal, Susana, Lopez-Sanz, Laura, Jimenez-Castilla, Luna, Carpio, Daniel, Droguett, Alejandra, Mezzano, Sergio, Egido, Jesús, Gomez-Guerrero, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352510/
https://www.ncbi.nlm.nih.gov/pubmed/32545818
http://dx.doi.org/10.3390/ijms21124225
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author Opazo-Ríos, Lucas
Plaza, Anita
Sánchez Matus, Yenniffer
Bernal, Susana
Lopez-Sanz, Laura
Jimenez-Castilla, Luna
Carpio, Daniel
Droguett, Alejandra
Mezzano, Sergio
Egido, Jesús
Gomez-Guerrero, Carmen
author_facet Opazo-Ríos, Lucas
Plaza, Anita
Sánchez Matus, Yenniffer
Bernal, Susana
Lopez-Sanz, Laura
Jimenez-Castilla, Luna
Carpio, Daniel
Droguett, Alejandra
Mezzano, Sergio
Egido, Jesús
Gomez-Guerrero, Carmen
author_sort Opazo-Ríos, Lucas
collection PubMed
description Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN.
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spelling pubmed-73525102020-07-15 Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy Opazo-Ríos, Lucas Plaza, Anita Sánchez Matus, Yenniffer Bernal, Susana Lopez-Sanz, Laura Jimenez-Castilla, Luna Carpio, Daniel Droguett, Alejandra Mezzano, Sergio Egido, Jesús Gomez-Guerrero, Carmen Int J Mol Sci Article Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN. MDPI 2020-06-13 /pmc/articles/PMC7352510/ /pubmed/32545818 http://dx.doi.org/10.3390/ijms21124225 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
Opazo-Ríos, Lucas
Plaza, Anita
Sánchez Matus, Yenniffer
Bernal, Susana
Lopez-Sanz, Laura
Jimenez-Castilla, Luna
Carpio, Daniel
Droguett, Alejandra
Mezzano, Sergio
Egido, Jesús
Gomez-Guerrero, Carmen
Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title_full Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title_fullStr Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title_full_unstemmed Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title_short Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy
title_sort targeting nf-κb by the cell-permeable nemo-binding domain peptide improves albuminuria and renal lesions in an experimental model of type 2 diabetic nephropathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352510/
https://www.ncbi.nlm.nih.gov/pubmed/32545818
http://dx.doi.org/10.3390/ijms21124225
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