<i>Cgnz1</i> allele confers kidney resistance to damage preventing progression of immune complex–mediated acute lupus glomerulonephritis

Ge, Yan; Jiang, Chao; Sung, Sun‐Sang J.; Bagavant, Harini; Dai, Chao; Wang, Hongyang; Kannapell, Carol C.; Cathro, Helen P.; Gaskin, Felicia; Fu, Shu Man

doi:10.1084/jem.20130731

Cited by 44 publications

(42 citation statements)

References 32 publications

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“…NZM2328 mice were originally purchased from the Jackson Laboratory [10], and R27 were generated by our laboratory [12]. Only female mice were used.…”

Section: Methodsmentioning

confidence: 99%

“…Serum BUN and urinary albumin/creatinine ratios were determined as described [12]. IgG, C3 and IgG2 deposition in kidneys by direct immunofluorescence, splenocyte cell surface marker expression by flow cytometry, serum anti-dsDNA antibodies by ELISA and ANA on 3T3 cells by immunofluores-cence were carried out as described [12]. Renal Ig eluates were used in Western blot analysis with kidney lysate from two month old NZM2328 as the substrate as described [12].…”

Section: Methodsmentioning

confidence: 99%

“…IgG, C3 and IgG2 deposition in kidneys by direct immunofluorescence, splenocyte cell surface marker expression by flow cytometry, serum anti-dsDNA antibodies by ELISA and ANA on 3T3 cells by immunofluores-cence were carried out as described [12]. Renal Ig eluates were used in Western blot analysis with kidney lysate from two month old NZM2328 as the substrate as described [12]. Two-tailed unpaired Student t-tests were used to evaluate the significance of the results with assigned p-values.…”

Section: Methodsmentioning

confidence: 99%

“…Our laboratory has used NZM2328 as a model for lupus nephritis (LN) [10–12]. LN and end stage renal disease (ESRD) develops preferentially in female mice in this model [10].…”

Section: Introductionmentioning

confidence: 99%

“…The phenotype of NZM2328.Lc4 is the development of LN and ESRD in female mice without ANA and anti-dsDNA antibodies, providing evidence that these antibodies are not required for the development of fatal LN [11]. Recently our laboratory generated a congenic strain NZM2328.Lc1R27 (R27) whose disease phenotype showed that chronic glomerulonephritis (GN) and immune complex-mediated acute GN are under separate genetic control and that immune complex-mediated GN need not progress to chronic GN leading to ESRD [12]. Studies of GN pathogenesis in NZM2328 and its congenic strain R27 now allow us to delineate the role of IFNα in LN.…”

Section: Introductionmentioning

confidence: 99%

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Interferon alpha on NZM2328.Lc1R27: Enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure

Dai

Wang

Sung

et al. 2014

Clinical Immunology

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Interferon alpha (IFNα) may play a significant role in systemic lupus erythematosus (SLE) pathogenesis. Recent literature suggests that IFNα does not correlate with disease activities and blockade of IFNα is not effective in treating SLE. This study aims to delineate further the role of IFNα in SLE. 12-week old NZM2328 and its congenic NZM2328.Lc1R27 (R27) female mice were challenged with adenovirus-IFNα (adeno-IFNα) or adenovirus-LacZ (adeno-LacZ). Only adeno-IFNα treated NZM2328 developed severe proteinuria and died of chronic glomerulonephritis (GN) and end stage renal disease. Adeno-IFNα treated R27 did develop immune complex-mediated GN but had normal renal function. Adeno-LacZ treated NZM2328 showed enlarged glomeruli and increased cellularity without immune complex deposition. Adeno-LacZ treated R27 did not show serological and histological abnormalities. Adeno-IFNα induced anti-dsDNA and anti-kidney autoantibodies in NZM2328 and R27. These results suggest that end organ damage is host-dependent and less related to autoimmunity and may have significant implications in SLE pathogenesis.

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“…NZM2328 mice were originally purchased from the Jackson Laboratory [10], and R27 were generated by our laboratory [12]. Only female mice were used.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Our laboratory has used NZM2328 as a model for lupus nephritis (LN) [10–12]. LN and end stage renal disease (ESRD) develops preferentially in female mice in this model [10].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interferon alpha on NZM2328.Lc1R27: Enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure

Dai

Wang

Sung

et al. 2014

Clinical Immunology

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Identification of Stage‐Specific Genes Associated With Lupus Nephritis and Response to Remission Induction in (NZB × NZW)F1 and NZM2410 Mice

Bethunaickan

Berthier

Zhang

et al. 2014

Arthritis & Rheumatology

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Objective To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission and relapse of nephritis in murine lupus models using transcriptome analysis. Methods Kidneys from NZB/W F1 and NZM2410 mice were harvested at intervals during their disease course or after remission induction. Genome wide expression profiles were obtained from microarray analysis of perfused kidneys. Real time PCR analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire dataset using singular value decomposition and self-organizing map were performed. Results Few changes in the renal molecular profile were detected in pre-nephritic kidneys but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all of the inflammatory changes and progression towards relapse was associated with recurrence of inflammation, mitochondrial dysfunction and metabolic stress signatures. Conclusion Immune cell infiltration and activation is associated with proteinuria onset and reverses with immunosuppressive therapy but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy of SLE nephritis may therefore need to target both immune and non-immune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in human lupus kidneys suggests potential new biomarkers and therapeutic targets.

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Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

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107

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Objective Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. This study investigates whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. Methods A fluorescence-labeled caspase-1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes in lupus-prone NZM2328 mice and in renal biopsies from LN patients. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, ultrastructure of podocytes and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line and cells were subjected to flow cytometry analysis. Results NLRP3 inflammasomes were activated in podocytes of lupus-prone mice and LN patients. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histological lesions and podocyte foot process effacement in lupus-prone mice. In vitro, sera from NZM2328 diseased mice activated NLRP3 inflammasomes in the podocyte cell line through reactive oxygen species (ROS) production. Conclusion NLRP3 inflammasomes were activated in podocytes of both LN patients and in lupus-prone mice. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.

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Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex–mediated acute lupus glomerulonephritis

Abstract: The mechanisms regulating acute and chronic glomerulonephritis are dependent on different genetic mechanisms, where the Cgnz1 allele confers kidney protection in immune complex–mediated proliferative lupus nephritis.

Cited by 44 publications

References 32 publications

Interferon alpha on NZM2328.Lc1R27: Enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure

Interferon alpha on NZM2328.Lc1R27: Enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure

Identification of Stage‐Specific Genes Associated With Lupus Nephritis and Response to Remission Induction in (NZB × NZW)F1 and NZM2410 Mice

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

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