Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells

Kunter, Uta; Daniel, Soizic; Arvelo, Maria B.; Choi, Jean Yu; Shukri, Tala; Patel, Virendra I.; Longo, Christopher R.; Scali, Salvatore T.; Shrikhande, Gautam; Rocha, Eduardo Melani; Czismadia, Eva; Mottley, Christina; Grey, Shane T.; Floege, Jürgen; Ferran, Christiane

doi:10.1111/j.1523-1755.2005.00564.x

Cited by 33 publications

(35 citation statements)

References 48 publications

(36 reference statements)

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“…Due to the serial appearance of different leukocytes in this model, it seems unlikely that this induction relates to a particular immune cell type [41]. A20 and SOCS3 are both expressed also by non-immune parenchymal cells and their induction may implicate the parenchyma’s attempt to minimize immunopathology [56,57]. It is noteworthy that SIGIRR was persistently downregulated throughout the injury and recovery phase, a finding that we had previously also demonstrated at the protein level [58].…”

Section: Resultsmentioning

confidence: 99%

Pattern-Recognition Receptor Signaling Regulator mRNA Expression in Humans and Mice, and in Transient Inflammation or Progressive Fibrosis

Günthner¹,

Kumar²,

Lorenz³

et al. 2013

IJMS

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The cell type-, organ-, and species-specific expression of the pattern-recognition receptors (PRRs) are well described but little is known about the respective expression profiles of their negative regulators. We therefore determined the mRNA expression levels of A20, CYLD, DUBA, ST2, CD180, SIGIRR, TANK, SOCS1, SOCS3, SHIP, IRAK-M, DOK1, DOK2, SHP1, SHP2, TOLLIP, IRF4, SIKE, NLRX1, ERBIN, CENTB1, and Clec4a2 in human and mouse solid organs. Humans and mice displayed significant differences between their respective mRNA expression patterns of these factors. Additionally, we characterized their expression profiles in mononuclear blood cells upon bacterial endotoxin, which showed a consistent induction of A20, SOCS3, IRAK-M, and Clec4a2 in human and murine cells. Furthermore, we studied the expression pattern in transient kidney ischemia-reperfusion injury versus post-ischemic atrophy and fibrosis in mice. A20, CD180, ST2, SOCS1, SOCS3, SHIP, IRAK-M, DOK1, DOK2, IRF4, CENTB1, and Clec4a2 were all induced, albeit at different times of injury and repair. Progressive fibrosis was associated with a persistent induction of these factors. Thus, the organ- and species-specific expression patterns need to be considered in the design and interpretation of studies related to PRR-mediated innate immunity, which seems to be involved in tissue injury, tissue regeneration and in progressive tissue scarring.

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Section: Resultsmentioning

confidence: 99%

Pattern-Recognition Receptor Signaling Regulator mRNA Expression in Humans and Mice, and in Transient Inflammation or Progressive Fibrosis

Günthner¹,

Kumar²,

Lorenz³

et al. 2013

IJMS

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“…However, we did not observe signs of activated apoptosis in RPTEC upon TNFα stimulation as demonstrated by absence of apoptotic DNA fragmentation, TUNEL positive chromatin, activation of caspase 3 or morphological changes in RPTEC corresponding to apoptosis. As has been published before, use of TNFα alone is not sufficient to induce apoptosis in RPTEC in vitro unless the cells are simultaneously treated with RNA and protein syntheses inhibitors [48]. This is explained by the fact that TNFα triggers two distinct signalling pathways leading either to apoptosis or to activation of NF-κB transcription factors which will inhibit apoptosis through expression of anti-apoptotic genes [49–51].…”

Section: Discussionmentioning

confidence: 99%

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

2015

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We have demonstrated that the renal endonuclease DNaseI is up-regulated in mesangial nephritis while down-regulated during progression of the disease. To determine the basis for these reciprocal DNaseI expression profiles we analyse processes accounting for an early increase in renal DNaseI expression. Main hypotheses were that i. the mesangial inflammation and secreted pro-inflammatory cytokines directly increase DNaseI protein expression in tubular cells, ii. the anti-apoptotic protein tumor necrosis factor receptor-associated protein 1 (Trap 1) is down-regulated by increased expression of DNaseI due to transcriptional interference, and iii. pro-inflammatory cytokines promote nuclear translocation of a variant of DNaseI. The latter hypothesis emerges from the fact that anti-DNaseI antibodies stained tubular cell nuclei in murine and human lupus nephritis. The present study was performed on human tubular epithelial cells stimulated with pro-inflammatory cytokines. Expression of the DNaseI and Trap 1 genes was determined by qPCR, confocal microscopy, gel zymography, western blot and by immune electron microscopy. Results from in vitro cell culture experiments were analysed for biological relevance in kidneys from (NZBxNZW)F1 mice and human patients with lupus nephritis. Central data indicate that stimulating the tubular cells with TNFα promoted increased DNaseI and reduced Trap 1 expression, while TNFα and IL-1β stimulation induced nuclear translocation of the DNaseI. TNFα-stimulation resulted in 3 distinct effects; increased DNaseI and IL-1β gene expression, and nuclear translocation of DNaseI. IL-1β-stimulation solely induced nuclear DNaseI translocation. Tubular cells stimulated with TNFα and simultaneously transfected with IL-1β siRNA resulted in increased DNaseI expression but no nuclear translocation. This demonstrates that IL-1β promotes nuclear translocation of a cytoplasmic variant of DNaseI since translocation clearly was not dependent on DNaseI gene activation. Nuclear translocated DNaseI is shown to be enzymatically inactive, which may point at a new, yet unknown function of renal DNaseI.

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“…We have identified A20 as a potent hepatoprotective protein that is part of the physiologic anti-apoptotic, anti-inflammatory and regenerative response of the liver [11], [21], [23], [37]. Overexpression of A20 in the liver afforded a significant survival and functional advantage in mouse models of extreme liver injury and resection.…”

Section: Discussionmentioning

confidence: 99%

A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

Damrauer

Studer²,

Silva³

et al. 2011

PLoS ONE

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BackgroundLiver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice.Methodology and Principal FindingsWe performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.βgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV.ConclusionThis Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients’ outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation.

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Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells

Cited by 33 publications

References 48 publications

Pattern-Recognition Receptor Signaling Regulator mRNA Expression in Humans and Mice, and in Transient Inflammation or Progressive Fibrosis

Pattern-Recognition Receptor Signaling Regulator mRNA Expression in Humans and Mice, and in Transient Inflammation or Progressive Fibrosis

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form

A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

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