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.
View: Text | PDF
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

×

Figure 6

PPTN protects kidney structure and renal tubules after IRI.

Options: View larger image (or click on image) Download as PowerPoint
PPTN protects kidney structure and renal tubules after IRI. (A) Kidney s...
(A) Kidney sections stained using H&E in SHAM 24 and 48 hours after IRI. Right panels show higher magnification of the regions delineated by the boxes in left panels. Severe alteration of renal tubule morphology is observed 24 and 48 hours after IRI in the DMSO group. Protection of kidney tubules is observed in the PPTN group versus DMSO at both time points after IRI. No effect of PPTN alone was observed in the SHAM group. Scale bar: 1 mm; inset scale bar: 100 μm. (B) Quantification of the percentage of intact tubules (green bars), moderately damaged tubules with detectable cellular structures (blue bars), and very damaged tubules with a complete loss of cell architecture (red bars). SHAM-DMSO (n = 7 mice), SHAM-PPTN (n = 10), IRI 24 hours DMSO (n = 7), IRI 24 hours PPTN (n = 6), IRI 48 hours DMSO (n = 7), IRI 48 hours PPTN (n = 8). IRI 24 hours DMSO vs. IRI 24 hours PPTN, *P = 0.029; IRI 48 hours DMSO vs. IRI 48 hours PPTN, *P = 0.016; by 2-way ANOVA followed by Tukey’s post hoc test. Between 940 and 1700 tubules were analyzed in each group.