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Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice
Maria Agustina Battistone, … , Dennis Brown, Sylvie Breton
Maria Agustina Battistone, … , Dennis Brown, Sylvie Breton
Published April 14, 2020
Citation Information: J Clin Invest. 2020;130(7):3734-3749. https://doi.org/10.1172/JCI134791.
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Research Article Inflammation Nephrology

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

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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 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.

Authors

Maria Agustina Battistone, Alexandra C. Mendelsohn, Raul German Spallanzani, Andrew S. Allegretti, Rachel N. Liberman, Juliana Sesma, Sahir Kalim, Susan M. Wall, Joseph V. Bonventre, Eduardo R. Lazarowski, Dennis Brown, Sylvie Breton

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Figure 1

Renal bilateral IRI increases urinary concentration of UDP-Glc.

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Renal bilateral IRI increases urinary concentration of UDP-Glc.
UDP-Glc ...
UDP-Glc was measured by LC-MS/MS in the urine of mice subjected to bilateral IRI and sham-operated mice. UDP-Glc concentration was normalized for urine creatinine (uCr). Each dot represents urine samples pooled from 3 mice. SHAM 2 hours, n = 7 samples (21 mice); SHAM 24 hours, n = 16 samples (48 mice); SHAM 48 hours, n = 6 samples (18 mice); IRI 2 hours, n = 13 samples (39 mice); IRI 24 hours, n = 7 samples (21 mice); IRI 48 hours, n = 6 samples (18 mice). Data are means ± SEM, analyzed using 2-way ANOVA followed by Tukey’s post hoc test. A significant elevation of UDP-Glc/uCr value was detected 2 hours after IRI compared with SHAM (IRI 2 hours vs. SHAM 2 hours, *P = 0.013). No difference was observed 24 hours and 48 hours after IRI. IRI 2 hours vs. IRI 24 hours, P = 0.0006; IRI 2 hours vs. IRI 48 hours, P = 0.0014.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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