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Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2302-E2310. doi: 10.1073/pnas.1716747115. Epub 2018 Feb 20.

Carbon monoxide protects the kidney through the central circadian clock and CD39.

Author information

1
Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
2
Hillhurst Biopharmaeuticals Inc., Montrose, CA 91020.
3
Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
4
Department of Chemistry, Georgia State University, Atlanta, GA 30303.
5
Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303.
6
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900, Sao Paulo, Brazil.
7
Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; lotterbe@bidmc.harvard.edu.

Abstract

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39-/- and Per2-/- mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

KEYWORDS:

DAMPS; adenosine; circadian rhythm; heme oxygenase; innate immunity

PMID:
29463714
PMCID:
PMC5877926
DOI:
10.1073/pnas.1716747115
[Indexed for MEDLINE]
Free PMC Article

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