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

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 2

Renal bilateral IRI increases expression of proinflammatory transcripts in ICs.

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Renal bilateral IRI increases expression of proinflammatory transcripts ...
(A) Representative pseudoblot of EGFP+ ICs isolated by FACS from kidney of B1-EGFP mice 2 hours after bilateral IRI. (B) qPCR showing expression of selected proinflammatory chemokines 2, 4, and 24 hours after IRI or sham surgery (SHM). Each dot represents 1 mouse. No difference was detected in SHM-operated mice (2, 4, and 24 hours), and all groups were then combined into a single SHM group. Data are means ± SEM, analyzed using 1-way ANOVA followed by Dunnett’s post hoc test. For Cxcl1, SHM (n = 8), IRI 2 hours (n = 8), IRI 4 hours (n = 5), IRI 24 hours (n = 6); **P = 0.0036, ****P < 0.0001. For Cxcl2, SHM (n = 6), IRI 2 hours (n = 10), IRI 4 hours (n = 6), IRI 24 hours (n = 6); *P = 0.034, ***P = 0.0009. For Ccl2, SHM (n = 8), IRI 2 hours (n = 6), IRI 4 hours (n = 6), IRI 24 hours (n = 6); *P = 0.018, ***P = 0.0006. For Il1b, SHM (n = 7), IRI 2 hours (n = 8), IRI 4 hours/24 hours (n = 6). For Il6, SHM (n = 7), IRI 2 hours (n = 10), IRI 4 hours/24 hours (n = 5). For Ccl3, SHM (n = 7), IRI 2 hours (n = 9), IRI 4 hours (n = 5), IRI 24 hours (n = 6). For Ccl4, SHM (n = 8), IRI 2 hours (n = 11), IRI 4 hours/24 hours (n = 6). For Tnf and Ccl5, SHM (n = 8), IRI 2 hours (n = 10), IRI 4 hours (n = 5), IRI 24 hours (n = 6). (C) Volcano plots (fold change [FC] vs. P value) of gene expression profiles of ICs, isolated by FACS 2 hours after IRI (IRI IC) versus SHAM (CTR IC). Each sample of RNA (n = 3) was obtained from a pool of 2 kidneys from 2 mice per group. Yellow lines show ± 2 FC. Genes upregulated after IRI are shown in red, genes downregulated after IRI in blue. Black dots represent transcripts that were not significantly differentially expressed. Data were analyzed using Student’s t test, 2 tailed.