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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MDPI AG
2024-03-01
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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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series | International Journal of Molecular Sciences |
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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