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 July 1, 2020; First 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 7

PPTN maintains PT polarity after IRI.

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PPTN maintains PT polarity after IRI. (A) Kidney sections labeled for AQ...
(A) Kidney sections labeled for AQP1 showed apical and basolateral localization in PTs from sham-operated mice. Twenty-four hours and 48 hours after IRI, a significant loss of AQP1 polarity was detected. In mice treated with PPTN, several PTs showed intact AQP1 localization at the brush border and basolateral membrane. PPTN alone did not affect AQP1 distribution in sham-operated mice. Scale bar: 1 mm; inset scale bar: 100 μm. (B) Quantification of the number of intact PTs with apical and basolateral AQP1 labeling (green bars), moderately damaged PTs with loss of apical labeling but detectable basolateral labeling (blue bars), and very damaged PTs with a complete loss of AQP1 polarity (red bars). PPTN induced a significant reduction in the number of very damaged PTs (IRI 24 hours DMSO [n = 8] vs. IRI 24 hours PPTN [n = 6] **P = 0.0043, IRI 48 hours DMSO [n = 11] vs. IRI 48 hours PPTN [n = 9] *P = 0.011) together with an increase in the number of intact PTs 24 hours and 48 hours after IRI (IRI 24 hours DMSO vs. IRI 24 hours PPTN *P = 0.026, IRI 48 hours DMSO vs. IRI 48 hours PPTN *P = 0.012, compared with the untreated group; SHAM-DMSO [n = 5], SHM-PPTN [n = 4]). Two-way ANOVA followed by Tukey’s post hoc test was performed. Between 1500 and 3000 PTs were analyzed in each group.