Induction of nitric oxide synthase in rat immune complex glomerulonephritis

Jansen, A.; Cook, Terence; Taylor, G. Michael; Largen, Penelope; Riveros‐Moreno, Valentina; Moncada, Salvador; Cattell, Victoria

doi:10.1038/ki.1994.161

Cited by 95 publications

(58 citation statements)

References 17 publications

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“…NO is overproduced in patients with inflammatory renal disease and animal models of lupus [32,33]. The mechanisms for the overproduction of NO remain unclear although IL-12 is required for NO production in MRL/lpr mice [10].…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

et al. 2006

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To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

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Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

et al. 2006

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“…2), the time during which there are functional changes (proteinuria) and beginning structural changes of chronic rejection (2,6). At 16 weeks, IL-2 first increases, followed by IL-2R expression at 24 weeks. An initial burst of IL-la and IL-6 occurs 5 days after transplantation during the acute rejection episode (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Nadeau

Azuma

Tilney

1995

Proc. Natl. Acad. Sci. U.S.A.

201

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Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection of renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon y] and macrophage (IL-la, tumor necrosis factor a, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

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“…Besides intrinsic renal cells, infiltrating granulocytes and macrophages in glomerular and tubulointerstitial lesions have been reported to be a distinct cellular source for iNOS production in human IgAN (18,48,49). In vitro, macrophage-activated iNOS expression can trigger apoptosis in cultured mesangial a Correlation was evaluated with spearman correlation coefficients.…”

Section: Discussionmentioning

confidence: 99%

Coupled Induction of iNOS and p53 Upregulation in Renal Resident Cells May Be Linked with Apoptotic Activity in the Pathogenesis of Progressive IgA Nephropathy

Qiu¹,

Sinniah

Hsu

2004

Journal of the American Society of Nephrology

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Abstract. In situ hybridization, immunohistochemistry, and TUNEL staining were applied to renal biopsy specimens of immunoglobulin A nephropathy (IgAN) patients to determine the expression of nitric oxide synthase (iNOS) (mRNA and protein), p53, and their potential roles in renal cell apoptosis in relation to the development of pathologic lesions. Fifty-one cases were categorized into four subgroups (A-D) according to the presence of progressive histopathological features. A cell type-specific and differential overexpression of iNOS mRNA and protein was dem-

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Induction of nitric oxide synthase in rat immune complex glomerulonephritis

Cited by 95 publications

References 17 publications

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

Coupled Induction of iNOS and p53 Upregulation in Renal Resident Cells May Be Linked with Apoptotic Activity in the Pathogenesis of Progressive IgA Nephropathy

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