Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

Thiyagarajan, Dhivya; Fismen, Silje; Seredkina, Natalya; Jacobsen, Søren; Elung-Jensen, Thomas; Kamper, Anne-Lise; Fenton, Christopher Graham; Rekvig, Ole Petter; Mortensen, Elin

doi:10.1371/journal.pone.0034080

Cited by 22 publications

(25 citation statements)

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“…We demonstrated that the expression of TLR7-9 and Clec4e was significantly upregulated in the BW mice at the same time when we observed the deposition of chromatin-IgG complexes in the GBM and the loss of renal DNaseI gene expression (68). We hypothesize that the presence of chromatin can be responsible for the increased TLR7-9/Clec4e expression.…”

Section: Biological Consequences Of Loss Of Dnasei Expression In Nephmentioning

confidence: 53%

“…The data are taken from murine and human parameters published by Thiyagarajan et al (68). These PCA biplots aim to display variances of the parameters.…”

Section: Biological Consequences Of Loss Of Dnasei Expression In Nephmentioning

confidence: 99%

“…Silencing of the DNaseI gene in kidneys during progression of lupus nephritis may be controlled by different mecha- D 1 9 : 1 6 1 -1 6 9 , 2 0 1 (68). PCA biplots aim to optimally display variances and not correlations.…”

Section: Aberrant Renal Dnasei Gene Expression In Lupus Nephritis: Pomentioning

confidence: 99%

“…The most striking observation in these biplots is that the DNaseI vector points away from the individuals with severe lupus nephritis (to the left in the biplots), demonstrating that loss of DNaseI correlates inversely with disease progression, whereas MMP-2, MMP-9, TLRs and EDSs associated with GBM are clustered and points at the most severely diseased murine and human individuals, in harmony with statistical analyses demonstrated by Thiyagarajan et al (68). This figure is modified from Thiyagarajan et al (68).…”

Section: Aberrant Renal Dnasei Gene Expression In Lupus Nephritis: Pomentioning

confidence: 99%

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Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

Seredkina

Vlag

Berden

et al. 2013

Mol Med

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Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex-mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNasel enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Down-regulation of DNasel expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals who produce IgG anti-chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNasel gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed.

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Section: Biological Consequences Of Loss Of Dnasei Expression In Nephmentioning

confidence: 53%

“…The data are taken from murine and human parameters published by Thiyagarajan et al (68). These PCA biplots aim to display variances of the parameters.…”

Section: Biological Consequences Of Loss Of Dnasei Expression In Nephmentioning

confidence: 99%

Section: Aberrant Renal Dnasei Gene Expression In Lupus Nephritis: Pomentioning

confidence: 99%

Section: Aberrant Renal Dnasei Gene Expression In Lupus Nephritis: Pomentioning

confidence: 99%

See 2 more Smart Citations

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

Seredkina

Vlag

Berden

et al. 2013

Mol Med

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“…DNAse-I is the major intra-renal endonuclease, responsible for more than 80% of the total intra-renal nuclease activity [18] . Unfortunately, in the diseased kidney, renal DNAse-I gene expression is silenced and DNAse-I activity downregulated [12,13,19,20] .…”

mentioning

confidence: 99%

Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury

Peer

Hamad²,

Berman³

et al. 2016

Am J Nephrol

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Background: Massive DNA destruction/accumulation of cell-free DNA debris is a sensitive biomarker of progressive organ/tissue damage. Deleterious consequences of DNA debris accumulation are evident in cardiac ischemia, thrombosis, auto-inflammatory diseases, SLE-induced lupus nephritis and cystic fibrosis. In case of renal pathologies, degradation and elimination of DNA debris are suppressed, due to downregulated DNAse-I activity within the diseased kidneys. The aim of the current study was to evaluate whether exogenous DNAse-I administration might exert renoprotective effects in the setting of acute kidney injury (AKI or acute renal failure). Methods: Sprague-Dawley rats underwent unilateral nephrectomy, with simultaneous clamping of contralateral kidney artery. The treated group received DNAse-I injection before discontinuing anesthesia. Positive (ischemic) controls received saline injection. Negative (non-ischemic) controls were either non-operated or subjected to surgery of similar duress and duration without ischemia. Renal perfusion was evaluated using the Laser-Doppler technique. Blood was procured for evaluating DNAse-I activity, renal functioning, renal perfusion. The kidneys were allocated for histopathologic examinations and for the evaluation of renal hypoxia, intra-renal apoptosis and proliferation. Results: Contrary to the situation in untreated ischemic rats, renal perfusion was significantly improved in DNAse-treated animals, concomitantly with significant amelioration of damage to renal functioning and tissue integrity. Treatment with DNAse-I significantly decreased the ischemia-induced renal hypoxia and apoptosis, simultaneously stimulating renal cell proliferation. Exogenous DNAse-I administration accelerated the clearance of intra-renal apoptotic DNA debris. Conclusion: Functional/histologic hallmarks of renal injury were ameliorated, renal functioning improved, intra-renal hypoxia decreased and intra-renal regeneration processes were activated. Thus, DNAse-I treatment protected the kidney from deleterious consequences of ischemia-induced AKI.

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The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved

Rekvig

Vlag

2014

Semin Immunopathol

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. A characteristic feature of SLE is the presence of autoantibodies against double-stranded (ds)DNA, histones and nucleosomes, and other chromatin components. SLE is a prototype type III hypersensitivity reaction. Local deposition of anti-nuclear antibodies in complex with released chromatin induces serious inflammatory conditions by activation of the complement system. The severe renal manifestation, lupus nephritis, is classified based on histological findings in renal biopsies. Apoptotic debris, including chromatin, is present in the extracellular matrix and circulation of patients with SLE. This may be due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells/chromatin. The non-cleared apoptotic debris may lead to activation of both the innate and adaptive immune systems. In addition, an aberrant presentation of peptides by antigen-presenting cells, disturbed selection processes for lymphocytes, and deregulated lymphocyte responses may be involved in the development of autoimmunity. In the present review, we briefly will summarize current knowledge on the pathogenesis of SLE. We will also critically discuss and challenge central issues that need to be addressed in order to fully understand the pathogenic mechanisms involved in the development of SLE and in order to have an improved diagnosis for SLE. Disappointingly, in our opinion, there are still more questions than answers for the pathogenesis, diagnosis, and treatment of SLE.

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Silencing of Renal DNaseI in Murine Lupus Nephritis Imposes Exposure of Large Chromatin Fragments and Activation of Toll Like Receptors and the Clec4e

Cited by 22 publications

References 58 publications

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

Lupus Nephritis: Enigmas, Conflicting Models and an Emerging Concept

Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury

The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved

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