BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.

Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injur...

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Autores: Saiz, Maria Laura, Lozano-Chamizo, Laura, Florez, Aida Bernardo, Marciello, Marzia, Diaz-Bulnes, Paula, Corte-Iglesias, Viviana, Bernet, Cristian Ruiz, Rodrigues-Diez, Raul R, Martin-Martin, Cristina, Rodriguez-Santamaria, Mar, Fernandez-Vega, Ivan, Rodriguez, Ramon M, Diaz-Corte, Carmen, Suarez-Alvarez, Beatriz, Filice, Marco, Lopez-Larrea, Carlos
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/20070
Acesso em linha:http://hdl.handle.net/20.500.12105/20070
Access Level:acceso abierto
Palavra-chave:Azepines
Reperfusion Injury
Triazoles
Renal Insufficiency, Chronic
Disease Progression
Mice, Inbred C57BL
Kidney
Liposomes
Bromodomain Containing Proteins
Nuclear Proteins
Animals
Mice
Male
Transcription Factors
Acute Kidney Injury
Disease Models, Animal
Nanoparticles
Cell Cycle Proteins
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spelling BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.Saiz, Maria LauraLozano-Chamizo, LauraFlorez, Aida BernardoMarciello, MarziaDiaz-Bulnes, PaulaCorte-Iglesias, VivianaBernet, Cristian RuizRodrigues-Diez, Raul RMartin-Martin, CristinaRodriguez-Santamaria, MarFernandez-Vega, IvanRodriguez, Ramon MDiaz-Corte, CarmenSuarez-Alvarez, BeatrizFilice, MarcoLopez-Larrea, CarlosAzepinesReperfusion InjuryTriazolesRenal Insufficiency, ChronicDisease ProgressionMice, Inbred C57BLKidneyLiposomesBromodomain Containing ProteinsNuclear ProteinsAnimalsMiceMaleTranscription FactorsAcute Kidney InjuryDisease Models, AnimalNanoparticlesCell Cycle ProteinsTargeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney-an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.ElsevierInstituto de Salud Carlos IIIUnión Europea. Comisión Europea. NextGenerationEUSociedad Española de NefrologíaGobierno del Principado de Asturias (España)Comunidad de Madrid (España)20242024-07-0420242024-05-0120242024-05-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/20070reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/200702026-06-12T12:43:37Z
dc.title.none.fl_str_mv BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
title BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
spellingShingle BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
Saiz, Maria Laura
Azepines
Reperfusion Injury
Triazoles
Renal Insufficiency, Chronic
Disease Progression
Mice, Inbred C57BL
Kidney
Liposomes
Bromodomain Containing Proteins
Nuclear Proteins
Animals
Mice
Male
Transcription Factors
Acute Kidney Injury
Disease Models, Animal
Nanoparticles
Cell Cycle Proteins
title_short BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
title_full BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
title_fullStr BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
title_full_unstemmed BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
title_sort BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.
dc.creator.none.fl_str_mv Saiz, Maria Laura
Lozano-Chamizo, Laura
Florez, Aida Bernardo
Marciello, Marzia
Diaz-Bulnes, Paula
Corte-Iglesias, Viviana
Bernet, Cristian Ruiz
Rodrigues-Diez, Raul R
Martin-Martin, Cristina
Rodriguez-Santamaria, Mar
Fernandez-Vega, Ivan
Rodriguez, Ramon M
Diaz-Corte, Carmen
Suarez-Alvarez, Beatriz
Filice, Marco
Lopez-Larrea, Carlos
author Saiz, Maria Laura
author_facet Saiz, Maria Laura
Lozano-Chamizo, Laura
Florez, Aida Bernardo
Marciello, Marzia
Diaz-Bulnes, Paula
Corte-Iglesias, Viviana
Bernet, Cristian Ruiz
Rodrigues-Diez, Raul R
Martin-Martin, Cristina
Rodriguez-Santamaria, Mar
Fernandez-Vega, Ivan
Rodriguez, Ramon M
Diaz-Corte, Carmen
Suarez-Alvarez, Beatriz
Filice, Marco
Lopez-Larrea, Carlos
author_role author
author2 Lozano-Chamizo, Laura
Florez, Aida Bernardo
Marciello, Marzia
Diaz-Bulnes, Paula
Corte-Iglesias, Viviana
Bernet, Cristian Ruiz
Rodrigues-Diez, Raul R
Martin-Martin, Cristina
Rodriguez-Santamaria, Mar
Fernandez-Vega, Ivan
Rodriguez, Ramon M
Diaz-Corte, Carmen
Suarez-Alvarez, Beatriz
Filice, Marco
Lopez-Larrea, Carlos
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Unión Europea. Comisión Europea. NextGenerationEU
Sociedad Española de Nefrología
Gobierno del Principado de Asturias (España)
Comunidad de Madrid (España)
dc.subject.none.fl_str_mv Azepines
Reperfusion Injury
Triazoles
Renal Insufficiency, Chronic
Disease Progression
Mice, Inbred C57BL
Kidney
Liposomes
Bromodomain Containing Proteins
Nuclear Proteins
Animals
Mice
Male
Transcription Factors
Acute Kidney Injury
Disease Models, Animal
Nanoparticles
Cell Cycle Proteins
topic Azepines
Reperfusion Injury
Triazoles
Renal Insufficiency, Chronic
Disease Progression
Mice, Inbred C57BL
Kidney
Liposomes
Bromodomain Containing Proteins
Nuclear Proteins
Animals
Mice
Male
Transcription Factors
Acute Kidney Injury
Disease Models, Animal
Nanoparticles
Cell Cycle Proteins
description Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney-an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-07-04
2024
2024-05-01
2024
2024-05-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/20070
url http://hdl.handle.net/20.500.12105/20070
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405312385024000
score 15.811543

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