Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (7), 3734-3749
- https://doi.org/10.1172/jci134791
Abstract
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 nephrotoxicants. Here, using a murine renal ischemia-reperfusion injury (IRI) model we show that intercalated cells (ICs) rapidly adopted a pro-inflammatory phenotype post-IRI. During the early phase of AKI, we demonstrate that either blocking the pro-inflammatory P2Y14 receptor located on the apical membrane of ICs, or ablation of the gene encoding the P2Y14 receptor in ICs: 1) inhibited IRI-induced chemokine expression increase in ICs; 2) reduced neutrophil and monocyte renal infiltration; 3) reduced the extent of kidney dysfunction; and 4) attenuated proximal tubule (PT) 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, uridine diphosphate-glucose (UDP-Glc), was higher in urine samples from intensive care unit patients who developed AKI compared to 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.Keywords
Funding Information
- National Institute of Health (HD040793)
- National Institute of Health- USA (5U54HL119145)
- National Institute of Health- USA (DK121848)
- National Institute of Health - USA (HL110873)
- American Heart Association (18CDA34110131)
- National Institute of Health (DK57521)
- National Institute of Health-USA (S10-OD-021577-01)
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