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Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors
Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366018/ https://www.ncbi.nlm.nih.gov/pubmed/35966871 http://dx.doi.org/10.3389/fmed.2022.931293 |
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author | Rosin, Diane L. Hall, J. Perry Zheng, Shuqiu Huang, Liping Campos-Bilderback, Silvia Sandoval, Ruben Bree, Andrea Beaumont, Kevin Miller, Emily Larsen, Jennifer Hariri, Ghazal Kaila, Neelu Encarnacion, Iain M. Gale, Jeremy D. van Elsas, Andrea Molitoris, Bruce A. Okusa, Mark D. |
author_facet | Rosin, Diane L. Hall, J. Perry Zheng, Shuqiu Huang, Liping Campos-Bilderback, Silvia Sandoval, Ruben Bree, Andrea Beaumont, Kevin Miller, Emily Larsen, Jennifer Hariri, Ghazal Kaila, Neelu Encarnacion, Iain M. Gale, Jeremy D. van Elsas, Andrea Molitoris, Bruce A. Okusa, Mark D. |
author_sort | Rosin, Diane L. |
collection | PubMed |
description | Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A(2A) receptor (A(2A)R) antagonist, was administered 1 h before bilateral IRI in WT, A(2A)R KO (Adora2a(–/–)) or CD73(–/–) mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a(–/–) mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73(–/–) mice, which lack a 5′-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A(2A)R-and non-A(2A)R-dependent signaling pathways. |
format | Online Article Text |
id | pubmed-9366018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93660182022-08-12 Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors Rosin, Diane L. Hall, J. Perry Zheng, Shuqiu Huang, Liping Campos-Bilderback, Silvia Sandoval, Ruben Bree, Andrea Beaumont, Kevin Miller, Emily Larsen, Jennifer Hariri, Ghazal Kaila, Neelu Encarnacion, Iain M. Gale, Jeremy D. van Elsas, Andrea Molitoris, Bruce A. Okusa, Mark D. Front Med (Lausanne) Medicine Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A(2A) receptor (A(2A)R) antagonist, was administered 1 h before bilateral IRI in WT, A(2A)R KO (Adora2a(–/–)) or CD73(–/–) mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a(–/–) mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73(–/–) mice, which lack a 5′-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A(2A)R-and non-A(2A)R-dependent signaling pathways. Frontiers Media S.A. 2022-07-28 /pmc/articles/PMC9366018/ /pubmed/35966871 http://dx.doi.org/10.3389/fmed.2022.931293 Text en Copyright © 2022 Rosin, Hall, Zheng, Huang, Campos-Bilderback, Sandoval, Bree, Beaumont, Miller, Larsen, Hariri, Kaila, Encarnacion, Gale, van Elsas, Molitoris and Okusa. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Rosin, Diane L. Hall, J. Perry Zheng, Shuqiu Huang, Liping Campos-Bilderback, Silvia Sandoval, Ruben Bree, Andrea Beaumont, Kevin Miller, Emily Larsen, Jennifer Hariri, Ghazal Kaila, Neelu Encarnacion, Iain M. Gale, Jeremy D. van Elsas, Andrea Molitoris, Bruce A. Okusa, Mark D. Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title | Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title_full | Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title_fullStr | Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title_full_unstemmed | Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title_short | Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors |
title_sort | human recombinant alkaline phosphatase (ilofotase alfa) protects against kidney ischemia-reperfusion injury in mice and rats through adenosine receptors |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366018/ https://www.ncbi.nlm.nih.gov/pubmed/35966871 http://dx.doi.org/10.3389/fmed.2022.931293 |
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