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
Entity
UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)Publisher
MDPI, Basel, SMwitzerlandDate
2020-06-13Citation
10.3390/ijms21124225
International Journal of Molecular Sciences 21.12 (2020): 4225
ISSN
1661-6596DOI
10.3390/ijms21124225Funded by
This work was supported by grants from: Fondecyt Project No 1160465 to S.M. and PhD CONICYT Grant No 21150768 to L.O-R.; Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; SAF2015-63696-R to C.G-G.), Ministry of Science and Innovation (MICINN/FEDER; RTI2018-098788-B-1I00 to C.G-G.) and Instituto de Salud Carlos III (FIS/FEDER; PI17/01495 and DTS-2017/00203 to J.E.)Project
Gobierno de España. PI17/01495; Gobierno de España. DTS-2017/00203Editor's Version
http://doi.org/10.3390/ijms21124225Subjects
Albuminuria; BTBR ob/ob mice; Diabetic nephropathy; Inflammation; NF-κB pathway; MedicinaRights
© 2020 The AuthorsAbstract
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.
Files in this item
Google Scholar:Opazo-Ríos, Lucas
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Plaza, Anita
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Matus, Yenniffer Sánchez
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Bernal, Susana
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Lopez-Sanz, Laura
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Jimenez-Castilla, Luna
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Carpio, Daniel
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Droguett, Alejandra
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Mezzano, Sergio
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Egido, Jesús
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Gómez Guerrero, Carmen
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