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 5

PPTN protects kidney function after IRI.

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PPTN protects kidney function after IRI. (A) Serum creatinine (sCr) over...
(A) Serum creatinine (sCr) over time after IRI in vehicle-treated mice (DMSO) versus PPTN. Each dot represents 1 mouse. SHM-DMSO (n = 24), SHM-PPTN (n = 18), IRI 2 hours DMSO (n = 14), IRI 2 hours PPTN (n = 7), IRI 24 hours DMSO (n = 8), IRI 24 hours PPTN (n = 6), IRI 48 hours DMSO (n = 10), IRI 48 hours PPTN (n = 10). **P = 0.0011, ****P < 0.0001. (B) BUN over time after IRI. Each dot represents 1 mouse. SHM-DMSO (n = 24), SHM-PPTN (n = 18), IRI 2 hours DMSO (n = 14), IRI 2 hours PPTN (n = 7), IRI 24 hours DMSO (n = 8), IRI 24 hours PPTN (n = 6), IRI 48 hours DMSO (n = 10), IRI 48 hours PPTN (n = 8). *P = 0.038, ****P < 0.0001. (C) Urine microalbumin/creatinine ratio (mALB/Cre) over time after IRI. Each dot represents urine collection from 3 mice. SHM-DMSO (n = 13, representing 39 mice), SHM-PPTN (n = 9; 27 mice), IRI 2 hours DMSO (n = 7; 21 mice), IRI 2 hours PPTN (n = 5; 15 mice), IRI 24 hours DMSO (n = 7; 21 mice), IRI 24 hours PPTN (n = 6; 18 mice), IRI 48 hours DMSO (n = 4; 12 mice), IRI 48 hours PPTN (n = 4; 12 mice). *P = 0.047, ****P < 0.0001. (D) Urinary concentration of KIM-1 over time after IRI. Each dot represents urine collection from 3 mice. SHM-DMSO (n = 6; 18 mice), SHM-PPTN (n = 6; 18 mice), IRI 24 hours DMSO (n = 6; 18 mice), IRI 48 hours PPTN (n = 3; 9 mice), IRI 48 hours DMSO (n = 4; 12 mice), IRI 48 hours PPTN (n = 3; 9 mice). *P = 0.041, ****P < 0.0001. For all graphs, data are means ± SEM, and 2-way ANOVA followed by Tukey’s test was performed.