ed1323831651926411d1f475b6e25deb pmc_33233484.pdf 69259df6b48890db28bafd8c8ba86abb5a98822b pmc_33233484.pdf fffd71ae3631d1a48b211f9bc1863e14be63fb8533a71943bf0e40ee61c39609 pmc_33233484.pdf Title: From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors Subject: 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-1 and other profibrotic markers, as well as CD163, C/EBP, and Col1A1, which are highly expressed in DD kidneys. TNF- mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-/NF-B pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-1 expression. In DD kidneys, the TNF-/NF-B pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-1 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. Keywords: fibrosis; macrophage; inflammation; transplant; kidney; purinome; adenosine receptor Author: Elena Guillén-Gómez, Irene Silva, Núria Serra, Francisco Caballero, Jesús Leal, Alberto Breda, Rody San Martín, Marçal Pastor-Anglada, José A. Ballarín, Lluís Guirado and Montserrat M. Díaz-Encarnación Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Mon Nov 23 06:48:56 2020 CET ModDate: Mon Nov 23 07:44:55 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2704203 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JDWIZJ+EURM10 Type 1 Builtin yes yes no 10 0 DIMMOC+VnURWPalladioL-Bold Type 1 Custom yes yes no 14 0 OHKNFJ+VnURWPalladioL Type 1 Custom yes yes no 19 0 ZKXJZH+URWPalladioL-Ital Type 1 Custom yes yes no 23 0 HTGQQM+URWPalladioL-Bold Type 1 Custom yes yes no 28 0 FLTUCD+URWPalladioL-Roma Type 1 Custom yes yes no 32 0 FATHTC+Rpxr Type 1 Builtin yes yes no 36 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 44 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Renal Tissue Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: THP-1 Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Western Blot Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Statistics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors Author: Elena Guillén-Gómez, Irene Silva, Núria Serra, Francisco Caballero, Jesús Leal, Alberto Breda, Rody San Martín, Marçal Pastor-Anglada, José A. Ballarín, Lluís Guirado and Montserrat M. Díaz-Encarnación Subject: 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-1 and other profibrotic markers, as well as CD163, C/EBP, and Col1A1, which are highly expressed in DD kidneys. TNF- mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-/NF-B pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-1 expression. In DD kidneys, the TNF-/NF-B pathway could be involved in the increase of A2AR expression, which would activate the PKA CREB axis, inducing the macrophage M2 phenotype, TGF-1 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. 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