Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice

Wang, S.; Yang, Niansheng; Zhang, L.; Huang, Bin; Tan, Hongna; Liang, Yong; Li, Y.; Yu, Xueqing

doi:10.1177/0961203310367660

Cited by 74 publications

(42 citation statements)

References 38 publications

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“…10 To determine if glycosphingolipid levels are detectable in the urine of lupus mice and how early in disease they are elevated with respect to albuminuria, urinary albumin and C 16 -LacCers (the most abundant species in the urine of mice; data not shown) were quantified in 24-hour urine collections from age-matched MRL/lpr and MRL/MpJ mice. As reported previously, 23 proteinuria increased at 16-18 weeks, with significant differences at 20 weeks ( Figure 6A). C 16 -LacCers increased at 14-16 weeks, with significant differences at 18 weeks ( Figure 6B).…”

Section: Renal Glycosphingolipid Dysfunction Begins Early In Disease supporting

confidence: 68%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

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Section: Renal Glycosphingolipid Dysfunction Begins Early In Disease supporting

confidence: 68%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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“…This original observation was supported further by studies directly showing activation of the STAT-1 pathway in kidney tissues obtained from autoimmune Murphy Roths large lymphoproliferation (MRL/lpr) mice and SLE patients [34,35]. Furthermore, inhibition of STAT-1 activation via targeting Janus kinase ameliorated the severity of lupus nephritis in an animal model and provided a potential therapeutic basis for SLE patients [36]. We note that the expression levels of STAT-1, but not miR-145, in SLE T cells was associated with lupus nephritis.…”

Section: Discussionmentioning

confidence: 86%

Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis

et al. 2012

Clinical and Experimental Immunology

109

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SummarySystemic lupus erythematosus (SLE) is a systemic autoimmune disease with abnormal T cell immune responses. We hypothesized that aberrant expression of microRNAs (miRNAs) in T cells may contribute to the pathogenesis of SLE. First, we analysed the expression profiles of 270 human miRNAs in T cells from five SLE patients and five healthy controls and then validated those potentially aberrant-expressed miRNAs using real-time polymerase chain reaction (PCR). Then, the expression of mRNAs regulated by these aberrantexpressed miRNAs was detected using real-time PCR. Finally, miRNA transfection into Jurkat T cells was conducted for confirming further the biological functions of these miRNAs. The initial analysis indicated that seven miRNAs, including miR-145, miR-224, miR-513-5p, miR-150, miR516a-5p, miR-483-5p and miR-629, were found to be potentially abnormally expressed in SLE T cells. After validation, under-expressed miR-145 and over-expressed miR-224 were noted. We further found that STAT1 mRNA targeted by miR-145 was over-expressed and apoptosis inhibitory protein 5 (API5) mRNA targeted by miR-224 was under-expressed in SLE T cells. Transfection of Jurkat cells with miR-145 suppressed STAT1 and miR-224 transfection suppressed API5 protein expression. Over-expression of miR-224 facilitates activation-induced cell death in Jurkat cells. In the clinical setting, the increased transcript levels of STAT1 were associated significantly with lupus nephritis. In conclusion, we first demonstrated that miR-145 and miR-224 were expressed aberrantly in SLE T cells that modulated the protein expression of their target genes, STAT1 and API5, respectively. These miRNA aberrations accelerated T cell activation-induced cell death by suppressing API5 expression and associated with lupus nephritis by enhancing signal transducer and activator of transcription-1 (STAT)-1 expression in patients with SLE.

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“…In our cGVHD model, expression of Stat3 in the mesangial cells of the Stat1-KO mice was associated with mesangial hyper-cellularity. Inhibiting renal expression of IFN-γ is accompanied by reduced infiltration of macrophages and attenuated deposition of IgG in the kidneys (33). Increased levels of IFN-γ in the glomeruli of Stat1-KO mice were associated with macrophage infiltration when cGVHD was induced.…”

Section: Discussionmentioning

confidence: 99%

Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

Shao

Gamero

Zhen

et al. 2015

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease, characterized by a spectrum of autoantibodies that target multiple cellular components. Glomerulonephritis is a major cause of morbidity in patients with SLE. Little is known about the pathogenesis of SLE renal damage and compromised renal function. Activation of both Stat1 and Stat3 has been reported in lupus and lupus nephritis. The reciprocal activation of these two transcription factors may have a major impact on renal inflammation. To study the role of Stat1 in a lupus model, we induced lupus-like chronic graft-versus-host disease (cGVHD) in Stat1-KO and in WT mice by intraperitoneal injection of class II-disparate bm12 splenocytes. WT recipients of these alloreactive cells developed anti-dsDNA autoantibodies starting at week 2 as expected, with a decline after week 4. In contrast, Stat1-KO hosts exhibited a prolonged and significant increase of anti-dsDNA autoantibody responses compared to WT mice (week 4 to week 8). Increased autoantibody titers were accompanied by increased proteinuria and mortality in the cGVHD host mice lacking Stat1. Further analysis revealed expression and activation of Stat3 in the glomeruli of Stat1-KO host mice but not WT mice with cGVHD. Glomerular Stat3 activity in the Stat1-KO mice was associated with increased IL-6 and IFN-γ secretion and macrophage infiltration. Interactions between Stat1 and Stat3 thus appear to be crucial in determining the severity of lupus-like disease in the cGVHD model.

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Jak/STAT signaling is involved in the inflammatory infiltration of the kidneys in MRL/lpr mice

Cited by 74 publications

References 38 publications

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis

Stat1 Regulates Lupus-like Chronic Graft-versus-Host Disease Severity via Interactions with Stat3

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