Expression of Fas, Bcl‐2 and p53 molecules in glomerulonephritis and their correlations with clinical and laboratory findings*

Uğuz, Aysun; Gönlüşen, Gülfiliz; Ergïn, Melek; Tuncer, İlhan

doi:10.1111/j.1440-1797.2005.00397.x

Cited by 18 publications

(15 citation statements)

References 39 publications

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“…A recent clinical study from Turkey correlated apoptosis in renal biopsies of patients with glomerulonephritis and clinical and laboratory findings [17]. Although this study used staining for Fas antigen-positive cells as markers of apoptosis, a significant increase in apoptotic cells was found in proliferative GN compared with nonproliferative cases, similar to our observations.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

DNA Fragmentation in Chronic Glomerulonephritis: An Immunohistological Analysis

Ott¹,

Aschoff

Pocock³

et al. 2006

Nephron Clin Pract

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Background: Experimental data suggest that apoptosis plays an important pathophysiological role in glomerulonephritis by restoring tissue structure after proliferation of intrinsic renal cells and infiltration of leukocytes. Relatively little is known of apoptosis in human glomerulonephritis, particularly in predicting renal function during follow-up. Methods: In order to colocalize different markers for cell damage in renal tissue from patients with different forms of glomerulonephritis (GN), a series of semithin sections from 34 kidney biopsies were studied retrospectively. Normal kidney from a nephrectomy specimen with a small renal adenocarcinoma served as a control. DNA fragmentation, expression of tissue transglutaminase II, BAX and BCL-2 were visualized immunohistochemically. In some renal biopsies, immunohistochemical staining for activated caspase 3 was performed. Proinflammatory markers (C-reactive protein, leukocytes), serum creatinine, creatinine clearance, total proteinuria, albuminuria, α₁-microglobulin and IgG excretion were determined at the time of biopsy. Serum creatinine and total proteinuria were assessed 6 and 12 months after renal biopsy. Results: Nuclei with different degrees of DNA fragmentation were mainly found in epithelial cells of tubules, but also in glomerular cells, regardless of the form of GN studied. Transglutaminase II expression was found only in cells with a strong staining for DNA fragmentation. DNA fragmentation localized to glomerular cells was more pronounced in proliferative than in non-proliferative forms of GN, being most abundant in patients with rapid progressive GN. Staining for activated caspase 3 in selected biopsies confirmed the presence of apoptosis. BAX and BCL-2 staining was detected within the same cells, but exhibited a different intracellular distribution. In proliferative GN, the extent of DNA damage in tubular epithelial cells significantly corresponds with the concentration of serum creatinine (p < 0.04) and with urinary excretion of α₁-microglobulin (p < 0.01) at the time of biopsy. A significant correlation (p < 0.01) was seen between glomerular DNA fragmentation and follow-up total proteinuria 12 months after biopsy for proliferative forms of GN. The damaged glomerular area (e.g. mesangial sclerosis) significantly correlated with DNA fragmentation in proliferative, but not in nonproliferative GN at the time of biopsy. Furthermore, glomerular damaged showed a significant correlation with tubular DNA damage in proliferative GN. Conclusion: In glomerular cells, apoptosis may be important for the clearance of proliferating cells whereas in tubules, cell damage showed dependence on the degree of tubular injury mediated by inflammation and/or proteinuria. Although the degree of apoptosis in tubular cells correlates with serum creatinine in proliferative GN at the time of biopsy, it is of limited use to predict future renal function.

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Section: Discussionsupporting

confidence: 87%

“…Moreover, in agreement with our observations, some degree of apoptosis was also present in nonproliferating forms of GN such as minimal change glomerulopathy, and no correlation was found between clinical and laboratory parameters of renal function and the degree of glomerular apoptosis. No follow-up was provided in this study [17]. …”

Section: Discussionmentioning

confidence: 99%

DNA Fragmentation in Chronic Glomerulonephritis: An Immunohistological Analysis

Ott¹,

Aschoff

Pocock³

et al. 2006

Nephron Clin Pract

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“…As both kidney cell proliferation and apoptosis have been described in LN (27)(28)(29), we assessed renal cell proliferation and apoptosis by Ki-67 and caspase 3 staining, respectively. Renal cell proliferation (seen in both glomerular and tubular compartments) increased significantly in bm12 injected B6 and B6KO mice ( p ϭ 0.0001 for each comparison to the respective control group).…”

Section: Fn14-deficient Mice Have Reduced Renal Igg Deposition Cytokmentioning

confidence: 99%

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Zhao

Burkly

Campbell

et al. 2007

The Journal of Immunology

144

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TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

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“…Fas activation prototypically depends on the adapter molecule, Fas-associated protein with death domain (FADD), to initiate caspase-8 proteolytic auto-cleavage, leading ultimately to activation of the effecter caspase, caspase-3, and cell death. Fas activation is implicated in the pathogenesis of a variety of disease conditions involving multiple organs, including the lungs [3][4][5], heart [6][7][8], and kidneys [9][10][11][12]. These findings have led to intense interest in pursuing anti-Fas and anti-apoptosis treatments as possible therapeutic interventions in clinical diseases associated with tissue injury.…”

Section: Introductionmentioning

confidence: 99%

Fas (CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway

Altemeier

Zhu

Berrington

et al. 2007

Journal of Leukocyte Biology

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Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of pro-inflammatory chemokines, leading to neutrophil recruitment and endorgan injury. The precise mechanism(s), by which Fas upregulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adapter molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88 −/− mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation.

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Expression of Fas, Bcl‐2 and p53 molecules in glomerulonephritis and their correlations with clinical and laboratory findings*

Cited by 18 publications

References 39 publications

DNA Fragmentation in Chronic Glomerulonephritis: An Immunohistological Analysis

DNA Fragmentation in Chronic Glomerulonephritis: An Immunohistological Analysis

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Fas (CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway

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