Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro Study

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3345
• Main Authors: Gallego-Tamayo, Beatriz, Santos-Aparicio, Ángela, Yago-Ibáñez, Julia, Muñoz-Moreno, Laura, Lucio-Cazaña, Francisco Javier, Fernández-Martínez, Ana B
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.03.2024; MDPI
• Subjects: acute kidney injury; Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - prevention & control; Cell death; Chemokines; Collagen; Communication; Coronavirus infections; cyclo-oxygenase-2; Cyclooxygenase 2 - metabolism; Cytokines; Cytoskeleton; Diabetes; diabetes mellitus; Diabetes Mellitus - drug therapy; Diabetics; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoxia; Inflammation; Kidneys; Leukocytes; Morphology; Permeability; prostaglandin E2; prostaglandin transporter; Prostaglandins; Sepsis; Sitagliptin; Type 2 diabetes; United Kingdom; Spain; prostaglandin E2; prostaglandin transporter; proximal tubular cells; dipeptidyl peptidase-4; acute kidney injury; diabetes mellitus; cyclo-oxygenase-2; sepsis
• DOI: 10.3390/ijms25063345
• ISSN: 1422-0067; 1661-6596

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 /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 (iPGE ); 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 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.