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 8

Deletion of P2Y14 in ICs protects kidney function, reduces inflammation, and attenuates damage after IRI.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of P2Y14 in ICs protects kidney function, reduces inflammation,...
(A) Left: ICs (CD117+CD45–; red dots) were isolated from B1Cre+ P2Y14fl/+ (IC KO) and B1Cre– P2Y14fl/+ (IC F/F; controls) mice. Right: P2ry14 expression by qPCR in IC KO versus IC F/F mice. ****P < 0.0001 by unpaired 2-tailed Student’s t test (n = 4). (B) sCr 24 hours after IRI versus SHAM in F/F and IC KO mice. *P = 0.031, ***P = 0.0008. (C) Recruitment of CD45+CD11b+Ly6G+ live cells 24 hours after IRI in F/F mice versus SHM (***P = 0.0003), and attenuation in IC KO mice (IRI KO vs. IRI F/F; *P = 0.041). (D) Recruitment of CD45+CD11b+Ly6C+Ly6G– live cells 24 hours after IRI in F/F versus SHM (****P < 0.0001), and attenuation in IC KO mice (IRI KO vs. IRI F/F; *P = 0.032). **P = 0.0014. (E) H&E staining of kidney of SHM and 24 hours after IRI in F/F and IC KO mice. Bar graph shows reduction of very damaged tubules (red bars; ***P = 0.0002) and increase in intact tubules (green bars; **P = 0.006) 24 hours after IRI in KO versus F/F mice. Scale bar: 50 μm. (F) AQP1 staining of kidney of SHAM and 24 hours after IRI in F/F and IC KO mice. Bar graph shows reduction of very damaged PTs (red bars; **P = 0.0012) and increase in intact PTs (green bars; **P = 0.0093) 24 hours after IRI in IC KO versus F/F. Scale bar: 50 μm; inset: 10 μm. Data are means ± SEM. Each dot represents 1 mouse. (B–D) One-way ANOVA followed by Tukey’s test. (E and F) Two-way ANOVA followed by Tukey’s test. (B–D) n = 5 for SHM F/F, SHM KO, and IRI KO; n = 6 for IRI F/F. (E) n = 6 for IRI F/F, SHM KO, and IRI KO; n = 7 for SHM F/F. (F) n = 6 mice for SHAM F/F, IRI 24 hours F/F, and IRI 24 hours KO; n = 5 for SHAM KO. Between 1400 and 2500 tubules were analyzed per group (E and F).