Impact of the Tumor Necrosis Factor Receptor-Associated Protein 1 (Trap1) on Renal DNaseI Shutdown and on Progression of Murine and Human Lupus Nephritis

Fismen, Silje; Thiyagarajan, Dhivya; Seredkina, Natalya; Nielsen, Henrik; Jacobsen, Søren; Elung-Jensen, Thomas; Kamper, Anne-Lise; Johansen, Steinar; Mortensen, Elin; Rekvig, Ole Petter

doi:10.1016/j.ajpath.2012.11.013

Cited by 21 publications

(22 citation statements)

References 41 publications

(64 reference statements)

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“…Our preliminary data on reciprocal expression of the two genes [29] are in agreement with experimental data on transcriptional interference [31,46,47]. However, in this study we dissected the independent effects of TNFα and IL-1β on DNaseI and Trap 1 regulation.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…If renal DNase I is lost, it cannot break down DNA as it appears in chromatin, and thus renal chromatin fragments may accumulate in the kidney. This and other studies have shown reduced renal DNase I expression and activity levels in mice [13] and in humans with advanced stages of lupus-like nephritis [26]. Here, we demonstrate reduced levels of DNase I in kidneys and urine in advanced stages of lupus nephritis in lupus-prone (NZB/NZW)F1 mice, as well as in human disease.…”

Section: Discussionsupporting

confidence: 81%

Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression

Pedersen

Horvei

Thiyagarajan

et al. 2018

The Journal of Pathology CR

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Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy. We further compared DNase I levels in human native and transplanted kidneys to determine if the disease depended on autologous renal genes, or whether the nephritic process proceeded also in transplanted kidneys. The data indicate that reduced renal DNase I expression level relates to serious progression of lupus nephritis in murine, human native, and transplanted kidneys. Notably, silencing of renal DNase I correlated with loss of DNase I endonuclease activity in the urine samples. Thus, urinary DNase I levels may therefore be used as a marker of lupus nephritis disease progression and reduce the need for renal biopsies.

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“…Since Trap1 acts as an anti‐apoptotic or survival protein and DNase1 as a death‐associated protein clearing dying cells, it is conceptually intriguing that the expression of two genes, which are linked to antagonistic processes, is mutually exclusive. An inverse correlation of DNase1 and Trap1 expression has been described in both the murine NZB/W F1 model and in kidneys of patients with diffuse‐proliferative lupus nephritis . In early mesangial nephritis Trap1 appears to be transiently upregulated followed by renal Dnase1 shutdown, while in end‐stage disease both genes are silenced.…”

Section: Discussionmentioning

confidence: 99%

Dnase1‐deficient mice spontaneously develop a systemic lupus erythematosus‐like disease

et al. 2019

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Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi‐organ damage. SLE is characterized by dysregulated activation of T‐ and B‐lymphocytes and the production of autoantibodies directed against nuclear components. The endonuclease deoxyribonuclease 1 (DNase1) is abundant in blood and a subset of SLE patients have mutations in DNASE1. Furthermore, a report showed that Dnase1‐deficient mice develop an SLE‐like disease, but these mice also carry a deletion of the gene adjacent to Dnase1, which encodes the chaperone TRAP1/HSP75. We generated a murine strain deficient in Dnase1 with an intact Trap1 gene to examine if a lack of DNase1 is responsible for the development of a spontaneous SLE‐like disease. We show that the Dnase1‐deficient mice do indeed develop an SLE‐like phenotype with elevated autoantibody production by 9 months and kidney damage by 12 months. Notably, this model recapitulates the female bias seen in human SLE patients since female Dnase1‐deficient mice produced the highest concentrations of autoantibodies and had more severe kidney damage than males. Since there is currently no cure for SLE the protective role of DNase1 as demonstrated in our study remains of great therapeutic interest.

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Impact of the Tumor Necrosis Factor Receptor-Associated Protein 1 (Trap1) on Renal DNaseI Shutdown and on Progression of Murine and Human Lupus Nephritis

Cited by 21 publications

References 41 publications

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

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

Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression

Dnase1‐deficient mice spontaneously develop a systemic lupus erythematosus‐like disease

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