Proximal Tubule CD73 Is Critical in Renal Ischemia-Reperfusion Injury Protection
| Autor: | Jürgen Schrader, Issah S. Vincent, Hong Ye, Li Li, Thu H. Le, Diane L. Rosin, Liping Huang, Jing Yu, Mark D. Okusa, Jessica R Lawler, Nicole Görldt, Sun-Sang J. Sung |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Adoptive cell transfer Ischemia Kidney Kidney Tubules Proximal Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Extracellular Animals Receptor 5'-Nucleotidase Cells Cultured Creatinine Chemistry General Medicine medicine.disease Adenosine Mice Inbred C57BL Basic Research 030104 developmental biology medicine.anatomical_structure Endocrinology Nephrology Reperfusion Injury Bone marrow 030215 immunology medicine.drug |
| Zdroj: | Journal of the American Society of Nephrology. 28:888-902 |
| ISSN: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2016020229 |
| Popis: | CD73-derived adenosine plays an anti-inflammatory role in various organs. However, its role in renal ischemia-reperfusion injury (IRI) is controversial. We targeted CD73 mutant mice to determine the function of CD73 expressed by various renal cell types under mild IRI conditions. Mice with CD73 deletion in proximal tubules exhibited exacerbated IRI, comparable with that of CD73−/− mice compared with WT mice. Mice with CD73 deletions in other cell types, including cortical type 1 fibroblast–like cells, mesangial cells, macrophages, and dendritic cells, showed small or no increases in injury above control mice when subjected to threshold levels of ischemia. Results from adoptive transfer experiments between WT and CD73−/− mice and pharmacologic studies modulating enzymatic activity of CD73 and extracellular adenosine levels supported a critical role of adenosine generated by proximal tubule CD73 expression in abrogating IRI. Renal adenosine levels were lower before and after ischemia in CD73-deficient mice. However, reduction in total acid–extractable renal adenosine levels was inadequate to explain the marked difference in kidney injury in these CD73-deficient mice. Furthermore, CD73 inhibition and enzyme replacement studies showed no change in total kidney adenosine levels in treated mice compared with vehicle-treated controls. Protection from IRI in neutrophil–depleted WT recipients was sustained by repopulation with bone marrow neutrophils from WT mice but not by those lacking adenosine 2a receptors (from Adora2a−/− mice). These data support the thesis that local adenosine generated by cells at the injury site is critical for protection from IRI through bone marrow–derived adenosine 2a receptors. |
| Databáze: | OpenAIRE |
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