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Open AccessArticle

From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors

1
Molecular Biology Laboratory, Fundació Puigvert, 08025 Barcelona, Spain
2
Nephrology Department, Fundació Puigvert, 08025 Barcelona, Spain
3
Institut Investigació Biosanitaria Sant Pau, Fundación Renal Iñigo Álvarez de Toledo (FRIAT), REDinREN, Autonomous University of Barcelona (UAB), 08025 Barcelona, Spain
4
Renal Transplant Unit, Fundació Puigvert, 08025 Barcelona, Spain
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Department of Emergency Medicine and Transplant Coordination, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain
6
Urology Department, Autonomous University of Barcelona (UAB), Fundació Puigvert, 08025 Barcelona, Spain
7
Molecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, 5110566 Valdivia, Chile
8
Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB), University of Barcelona, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), 08028 Barcelona, Spain
9
Institut de Recerca Sant Joan de Déu (IR SJD), 08950 Esplugues de Llobregat Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8826; https://doi.org/10.3390/ijms21228826
Received: 15 October 2020 / Revised: 16 November 2020 / Accepted: 20 November 2020 / Published: 21 November 2020
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants. View Full-Text
Keywords: fibrosis; macrophage; inflammation; transplant; kidney; purinome; adenosine receptor fibrosis; macrophage; inflammation; transplant; kidney; purinome; adenosine receptor
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Guillén-Gómez, E.; Silva, I.; Serra, N.; Caballero, F.; Leal, J.; Breda, A.; San Martín, R.; Pastor-Anglada, M.; Ballarín, J.A.; Guirado, L.; Díaz-Encarnación, M.M. From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors. Int. J. Mol. Sci. 2020, 21, 8826.

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