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 3

Inhibition of P2Y14 with PPTN attenuates IC-specific upregulation of proinflammatory chemokines induced by IRI.

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Inhibition of P2Y14 with PPTN attenuates IC-specific upregulation of pro...
(A) Concentration of PPTN, a specific P2Y14 antagonist, in the urine of mice treated with a single i.v. injection corresponding to 0.18 mg/kg (2 hours), or via continuous infusion with ALZET osmotic minipumps implanted s.c. for 24 or 48 hours corresponding to a dose of 4.55 mg/kg/d, versus controls (CTR; treated with vehicle only). PPTN urinary concentration was measured using LC-MS/MS. Data are means ± SEM analyzed using 1-way ANOVA and Dunnett’s test. CTR vs. 4.55 mg/kg/d 24 hours ***P = 0.0007; CTR vs. 4.55 mg/kg/d 48 hours ***P = 0.0006. (B) qPCR analysis of selected chemokines in ICs isolated by FACS 2 hours after IRI versus SHAM. PPTN-treated mice received a dose of 4.55 mg/kg/d through osmotic minipumps, while nontreated mice received vehicle. Data are means ± SEM, analyzed by 1-way ANOVA and Tukey’s test. No difference in chemokine expression was detected between the SHAM-vehicle and SHAM-PPTN groups, which were then combined into a single SHAM group (SHM). Some IRI groups are the same as those shown in Figure 2B (IRI 2 hours). Each dot represents 1 mouse. For Cxcl1, SHM (n = 6), IRI (n = 8), IRI-PPTN (n = 8); **P = 0.0039, ***P = 0.0002, ****P < 0.0001. For Cxcl2, SHM (n = 6), IRI (n = 10), IRI-PPTN (n = 8); *P = 0.013, ****P < 0.0001. For Ccl2, SHM (n = 8), IRI (n = 8), IRI-PPTN (n = 8); **P = 0.0092, ***P = 0.0005. For Il1b, SHM (n = 7) vs. IRI (n = 8) ***P = 0.0006; IRI vs. IRI-PPTN (n = 8) ***P = 0.0006. For Il6, SHM (n = 7), IRI (n = 10), IRI-PPTN (n = 8); *P = 0.042. For Cxcl10, SHM (n = 4), IRI (n = 6), IRI-PPTN (n = 7); *P = 0.015. For Tnf, SHM (n = 9), IRI (n = 10), IRI-PPTN (n = 8). For Il34, SHM (n = 4), IRI (n = 6), IRI-PPTN (n = 7). For Il1f6, SHM (n = 3), IRI (n = 5), IRI-PPTN (n = 6).