Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/ hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs...

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Autores: Gallego Tamayo, Beatriz, Santos Aparicio, Angela, Yago Ibáñez, Julia, Muñoz Moreno, Laura, Lucio Cazaña, Francisco Javier, Fernández Martínez, Ana Belén
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/714129
Acceso en línea:http://hdl.handle.net/10486/714129
https://dx.doi.org/10.3390/ijms25063345
Access Level:acceso abierto
Palabra clave:Acute kidney injury
Cyclo-oxygenase-2
Diabetes mellitus
Dipeptidyl peptidase-4
Prostaglandin E2
Prostaglandin transporter
Proximal tubular cells
Sepsis
Biología y Biomedicina / Biología
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spelling Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro studyGallego Tamayo, BeatrizSantos Aparicio, AngelaYago Ibáñez, JuliaMuñoz Moreno, LauraLucio Cazaña, Francisco JavierFernández Martínez, Ana BelénAcute kidney injuryCyclo-oxygenase-2Diabetes mellitusDipeptidyl peptidase-4Prostaglandin E2Prostaglandin transporterProximal tubular cellsSepsisBiología y Biomedicina / BiologíaThe probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/ hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25mMglucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKIThis research is part of the project on COVID-19 and diabetes (REACT UE-CM2021-02), funded by the Community of Madrid in agreement with the University of Alcalá, and co-funded with REACT-EU resources from the European Regional Development Fund «A way to make Europe». It was also funded by the Comunidad de Madrid I+D Biomedicine Activities Program 2022 (project P2022/BMD7223 CIFRA_COR_CM). Angela Santos Aparicio is a Research Assistant trainee funded by the Programa Operativo de Empleo Juvenil of the Comunidad Autónoma de Madrid (Ref. PEJ- 2021-AI/BMD-23368), which is co-funded by the Youth Employment Initiative (YEI) from the Youth Guarantee Programme (European Social Fund, EU)MDPIDepartamento de BiologíaFacultad de Ciencias20242024-03-15research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/714129https://dx.doi.org/10.3390/ijms25063345reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7141292026-06-23T12:46:27Z
dc.title.none.fl_str_mv Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
title Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
spellingShingle Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
Gallego Tamayo, Beatriz
Acute kidney injury
Cyclo-oxygenase-2
Diabetes mellitus
Dipeptidyl peptidase-4
Prostaglandin E2
Prostaglandin transporter
Proximal tubular cells
Sepsis
Biología y Biomedicina / Biología
title_short Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
title_full Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
title_fullStr Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
title_full_unstemmed Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
title_sort Prostaglandin transporter and dipeptidyl peptidase-4 as new pharmacological targets in the prevention of acute kidney injury in diabetes: an In Vitro study
dc.creator.none.fl_str_mv Gallego Tamayo, Beatriz
Santos Aparicio, Angela
Yago Ibáñez, Julia
Muñoz Moreno, Laura
Lucio Cazaña, Francisco Javier
Fernández Martínez, Ana Belén
author Gallego Tamayo, Beatriz
author_facet Gallego Tamayo, Beatriz
Santos Aparicio, Angela
Yago Ibáñez, Julia
Muñoz Moreno, Laura
Lucio Cazaña, Francisco Javier
Fernández Martínez, Ana Belén
author_role author
author2 Santos Aparicio, Angela
Yago Ibáñez, Julia
Muñoz Moreno, Laura
Lucio Cazaña, Francisco Javier
Fernández Martínez, Ana Belén
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biología
Facultad de Ciencias
dc.subject.none.fl_str_mv Acute kidney injury
Cyclo-oxygenase-2
Diabetes mellitus
Dipeptidyl peptidase-4
Prostaglandin E2
Prostaglandin transporter
Proximal tubular cells
Sepsis
Biología y Biomedicina / Biología
topic Acute kidney injury
Cyclo-oxygenase-2
Diabetes mellitus
Dipeptidyl peptidase-4
Prostaglandin E2
Prostaglandin transporter
Proximal tubular cells
Sepsis
Biología y Biomedicina / Biología
description The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/ hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25mMglucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-03-15
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
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/10486/714129
https://dx.doi.org/10.3390/ijms25063345
url http://hdl.handle.net/10486/714129
https://dx.doi.org/10.3390/ijms25063345
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 4.0 International
http://creativecommons.org/licenses/by/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 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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