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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Main Authors: Beatriz Gallego-Tamayo, Ángela Santos-Aparicio, Julia Yago-Ibáñez, Laura Muñoz-Moreno, Francisco Javier Lucio-Cazaña, Ana B. Fernández-Martínez
Format: Article
Language:English
Published: MDPI AG 2024-03-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/25/6/3345
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author Beatriz Gallego-Tamayo
Ángela Santos-Aparicio
Julia Yago-Ibáñez
Laura Muñoz-Moreno
Francisco Javier Lucio-Cazaña
Ana B. Fernández-Martínez
author_facet Beatriz Gallego-Tamayo
Ángela Santos-Aparicio
Julia Yago-Ibáñez
Laura Muñoz-Moreno
Francisco Javier Lucio-Cazaña
Ana B. Fernández-Martínez
author_sort Beatriz Gallego-Tamayo
collection DOAJ
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% O<sub>2</sub>/25 mM glucose/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 E<sub>2</sub> (iPGE<sub>2</sub>); 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 PGE<sub>2</sub> 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.
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spelling doaj.art-620808f17cd848cd91c607fe515d9ada2024-03-27T13:45:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256334510.3390/ijms25063345Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro StudyBeatriz Gallego-Tamayo0Ángela Santos-Aparicio1Julia Yago-Ibáñez2Laura Muñoz-Moreno3Francisco Javier Lucio-Cazaña4Ana B. Fernández-Martínez5Universidad de Alcalá, Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Campus Universitario, Crtra A2, Km. 33,600, 28805 Alcalá de Henares, SpainUniversidad de Alcalá, Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Campus Universitario, Crtra A2, Km. 33,600, 28805 Alcalá de Henares, SpainDepartamento de Biología, Universidad Autónoma de Madrid, 28049 Madrid, SpainUniversidad de Alcalá, Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Campus Universitario, Crtra A2, Km. 33,600, 28805 Alcalá de Henares, SpainUniversidad de Alcalá, Departamento de Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud, Campus Universitario, Crtra A2, Km. 33,600, 28805 Alcalá de Henares, SpainDepartamento de Biología, Universidad Autónoma de Madrid, 28049 Madrid, SpainThe 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% O<sub>2</sub>/25 mM glucose/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 E<sub>2</sub> (iPGE<sub>2</sub>); 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 PGE<sub>2</sub> 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.https://www.mdpi.com/1422-0067/25/6/3345acute kidney injurycyclo-oxygenase-2diabetes mellitusdipeptidyl peptidase-4prostaglandin E2prostaglandin transporter
spellingShingle Beatriz Gallego-Tamayo
Ángela Santos-Aparicio
Julia Yago-Ibáñez
Laura Muñoz-Moreno
Francisco Javier Lucio-Cazaña
Ana B. Fernández-Martínez
Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro Study
International Journal of Molecular Sciences
acute kidney injury
cyclo-oxygenase-2
diabetes mellitus
dipeptidyl peptidase-4
prostaglandin E2
prostaglandin transporter
title 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_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_sort prostaglandin transporter and dipeptidyl peptidase 4 as new pharmacological targets in the prevention of acute kidney injury in diabetes an in vitro study
topic acute kidney injury
cyclo-oxygenase-2
diabetes mellitus
dipeptidyl peptidase-4
prostaglandin E2
prostaglandin transporter
url https://www.mdpi.com/1422-0067/25/6/3345
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