Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice

Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery, or exposure to nephrotoxins. Here, using a murine renal ischemia/reperfusion injury (IRI) model, we show that intercalated cells (...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-07, Vol.130 (7), p.3734-3749
Main Authors: Battistone, Maria Agustina, Mendelsohn, Alexandra C, Spallanzani, Raul German, Allegretti, Andrew S, Liberman, Rachel N, Sesma, Juliana, Kalim, Sahir, Wall, Susan M, Bonventre, Joseph V, Lazarowski, Eduardo R, Brown, Dennis, Breton, Sylvie
Format: Article
Language:English
Subjects:
Ablation
Acute Kidney Injury - genetics
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Acute Kidney Injury - prevention & control
Animals
Binding sites
Biomedical research
Cardiac patients
Chemokines
Chemokines - biosynthesis
Chemokines - genetics
Gene expression
Glucose
Heart
Heart surgery
Inflammation
Intensive care
Ischemia
Ischemia - genetics
Ischemia - metabolism
Ischemia - pathology
Ischemia - prevention & control
Kidney - blood supply
Kidney - metabolism
Kidney - pathology
Kidney diseases
Kidneys
Mice
Mice, Knockout
Monocytes
Monocytes - metabolism
Monocytes - pathology
Neutrophil Infiltration
Neutrophils
Neutrophils - metabolism
Neutrophils - pathology
Patients
Pattern recognition
Phenotypes
Prevention
Receptors, Purinergic P2Y - genetics
Receptors, Purinergic P2Y - metabolism
Reperfusion
Sepsis
Urine
Uterus
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Description
Summary:Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery, or exposure to nephrotoxins. Here, using a murine renal ischemia/reperfusion injury (IRI) model, we show that intercalated cells (ICs) rapidly adopted a proinflammatory phenotype after IRI. Wwe demonstrate that during the early phase of AKI either blockade of the proinflammatory P2Y14 receptor located on the apical membrane of ICs or ablation of the gene encoding the P2Y14 receptor in ICs (a) inhibited IRI-induced increase of chemokine expression in ICs, (b) reduced neutrophil and monocyte renal infiltration, (c) reduced the extent of kidney dysfunction, and (d) attenuated proximal tubule damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand UDP-glucose (UDP-Glc) was higher in urine samples from intensive care unit patients who developed AKI compared with patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic AKI.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI134791