Adenosine mediates transforming growth factor‐beta 1 release in kidney glomeruli of diabetic rats

Roa, Horacio; Gajardo, C.; Troncoso, E.; Fuentealba, Victorino; Escudero, Carlos; Yáñez, Alejandro J.; Sobrevía, Luis; Pastor‐Anglada, Marçal; Quezada, Claudia; Martin, R. H.

doi:10.1016/j.febslet.2009.09.003

Cited by 40 publications

(58 citation statements)

References 36 publications

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“…This effect could be linked to a decreased activity of ENT1 measured in isolated diabetic glomeruli. 22 Similar to our finding, ENT1 activity was found to be decreased in human endothelial cells isolated from gestational diabetes pregnancy 43 or in cells exposed to high glucose concentrations. 44,45 This decreased activity of ENT1 elicits adenosine signaling by ARs as previously described, using inhibitors of ENT1 activity or in ENT1 À / À mice.…”

Section: Discussionsupporting

confidence: 79%

“…33 Therefore, currently strategies for DN therapy may need to involve interception of both the TGFb and the VEGF signaling pathways. In this way, the A 2B AR antagonist could be a valuable tool because it was demonstrated that it is able to block the increased release of TGF-b from diabetic glomeruli in vitro 22 and the myofibroblast transdifferentiation of masangial cells in vivo, as reported in this work. Similarly, interception of VEGF induction was a remarkable feature.…”

Section: Discussionmentioning

confidence: 65%

“…22 For determination of the urinary nucleoside levels the urines of rats were recollected in metabolic cages for 24 h. Samples were processed according to previously described 29 and derivatized for HPLC analysis.…”

Section: Adenosine Mediates Diabetic Glomerulopathymentioning

confidence: 99%

“…Immunodetection was performed as described previously 22 using the primary anti-A 2B AR, anti-A 1 AR, anti-VEGF and anti-nephrin polyclonal antibodies (ab40002, ab46154 and ab58968 from Abcam), and the monoclonal anti-a-smooth muscle actin (aSMA) (sc130617 from Santa Cruz Biotechnology, Santa Cruz, CA, USA). The immunosignals were revealed using the LSAB þ System-HRP system (Dako, Carpinteria, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…[15][16][17][18][19][20][21] ENTs activity mediates adenosine uptake to be either metabolized intracellularly, or to accumulate outside when the uptake activity is reduced. We have previously determined that the ENT1's activity decreased in diabetic rats' glomeruli 22 therefore, the handling of the nucleoside could be altered in this pathologic condition.…”

mentioning

confidence: 99%

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Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A 2B receptor (A 2B AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCa and Erk1/2 activation. The glomerular content of A 2B AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A 2B AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 65%

Section: Adenosine Mediates Diabetic Glomerulopathymentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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Adenosine signaling inhibits CIITA‐mediated MHC class II transactivation in lung fibroblast cells

Fang

Xia

et al. 2013

Eur J Immunol

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Keywords: Adenosine A2b signaling r CIITA r Epigenetics r MHC class II r Transcriptional regulation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAntigen-restricted activation of T lymphocytes, which are designed to eliminate intracellular pathogens, plays a critical role in adapCorrespondence: Dr. Yong Xu e-mail: yxu2005@gmail.com tive immunity [1]. By their expression of major histocompatibility complex (MHC) molecules, two groups of cells are specialized in presenting processed antigen to T cells: professional antigen presenting cells (p-APCs), which include B cells, dendritic cells, * These authors contributed equally to this work. . Efficient antigen presentation serves several critical pathobiological purposes. One of them is to combat the invasion of opportunistic microbes. Indeed, defective expression of MHC II molecules in fibroblast cells is associated with increased incidence of bacterial and viral infection [5]. Another example whereby the MHC II-dependent immune response plays a predominant role in host defense is the recognition and killing of cancer cells that express foreign epitopes. Mounting evidence has suggested that malignant cells employ a range of strategies to manipulate MHC II expression by fibroblast cells to facilitate evasion [6,7].Adenosine signaling is one of the biologically conserved pathways in mammals that regulates a range of life activities [8]. Recent investigations, however, reveal that adenosine signaling promotes carcinogenesis [9] and infectious diseases [10], indicating that it may target CIITA-mediated MHC II transactivation. Here, we report that adenosine signaling through the A2b receptor downregulates MHC II expression in lung fibroblast cells by repressing CIITA transcription via type III and IV promoters. Our data provide a novel rationale for the blockade of A2b adenosine signaling in the treatment of cancer and infectious disease. Results Adenosine signaling represses MHC II transcriptionWe have previously shown that MHC II expression is inducible by IFN-γ in lung fibroblast cells (IMR-90) in a CIITA-dependent manner [11]. To determine whether adenosine signaling could suppress MHC II expression, we treated IMR-90 cells with an adenosine receptor agonist adenosine-5 N-ethylcarboxamide (NECA). NECA downregulated the induction of HLA-DRα by IFN-γ at both mRNA (Fig. 1A) and protein (Fig. 1B) levels in a dose-response fashion. To examine whether the repression of MHC II expression by NECA took place at the transcription level, an HLA-DR-α promoter-reporter fusion construct was transfected into IMR-90 cells. As shown in Figure 1C, IFN-γ activated the promoter activity but NECA dampened the activation. Similar observations were made in primary mouse lung fibroblast cells (Supporting Information Fig. 1A and B). Therefore, activation of adenosine signaling in lung fibroblast cells is associated with attenuated MHC II transactivation by IFN-γ. Adenosine signaling represses CIITA expression via ...

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New role of the human equilibrative nucleoside transporter 1 (hENT1) in Epithelial‐to‐mesenchymal transition in renal tubular cells

Guillén‐Gómez

Pinilla-Macua

Pérez-Torras

et al. 2012

Journal Cellular Physiology

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Epithelial-to-mesenchymal transition (EMT) is an important pro-fibrotic event in which tubular epithelial cells are transformed into myofibroblasts. Nucleoside transporters (NT) are regulated by many factors and processes, some of which are involved in fibrosis, such as cytokines, inflammation, and proliferation. Equilibrative nucleoside transporter 1 (ENT1) has been proved to be the most widely expressed adenosine transporter. In that sense, ENT1 may be a key player in cell damage signaling. Here we analyze the role of human ENT1 (hENT1) in the EMT process in proximal tubular cells. Addition of the main inducer of EMT, the transforming growth factor-β1, to HK-2 cells increased hENT1 mRNA and protein level expression. ENT1-mediated adenosine uptake was also enhanced. When cells were incubated with dipyridamole to evaluate the potential contribution of ENT1 to EMT by blocking its transport activity, EMT was induced. Moreover, the knock down of hENT1 with siRNA induced EMT and collagen production in HK-2 cells. Kidneys isolated from ENT1 knockout mice showed higher levels of interstitial collagen and α-SMA positive cells than wild-type mice. Our results point to a new potential role of hENT1 as a modulator of EMT in proximal tubular cells. In this sense, hENT1 could be involved in renal protection processes, and the loss or reduced expression of hENT1 would lead to an increased vulnerability of cells to the onset and/or progression of renal fibrosis.

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Adenosine mediates transforming growth factor‐beta 1 release in kidney glomeruli of diabetic rats

Cited by 40 publications

References 36 publications

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Adenosine signaling inhibits CIITA‐mediated MHC class II transactivation in lung fibroblast cells

New role of the human equilibrative nucleoside transporter 1 (hENT1) in Epithelial‐to‐mesenchymal transition in renal tubular cells

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