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  • 1
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: Studies in experimental models have established that blockade of either interleukin 1 (IL-1) or tumour necrosis factor α (TNF-α) is effective in suppressing crescentic glomerulonephritis. However, it is not known whether simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We have addressed this question in a study of accelerated crescentic anti-glomerular basement membrane (GBM) glomerulonephritis in the rat. Groups of six animals were treated with an IL-1 receptor antagonist (IL-1ra), TNF-α-binding protein (TNFbp), IL-1ra + TNFbp (combined) or saline (control) from the time of anti-GBM serum injection until being killed, 10 days later. Saline-treated animals developed crescentic glomerulonephritis with tubulointerstitial damage, heavy proteinuria and renal impairment. Compared with saline, treatment with either IL-1ra or TNFbp alone resulted in significant suppression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; both P 〈 0.001 vs. control), tubulointerstitial leucocytic infiltration (262 ± 31 and 282 ± 32 cells/mm2 vs. 481 ± 71 cells/mm2; both P 〈 0.001 vs. control) and proteinuria (167 ± 44 and 164 ± 23 mg/24 h vs. 279 ± 36 mg/24 h; both P 〈 0.001 vs. control) and prevented the loss of renal function. Combined IL-1ra and TNFbp treatment resulted in a virtually identical degree of disease suppression as individual cytokine blockade in terms of crescent formation (2.7%), interstitial leucocytic infiltration (274 ± 45 cells/mm2), proteinuria (190 ± 18 mg/24 h) and renal function preservation. In conclusion, this study has demonstrated that blockade of either IL-1 or TNF-α alone substantial suppresses experimental crescentic glomerulonephritis to a similar extent to that achieved by simultaneous blockade of both cytokines. These findings provide a rationale for the use of cytokine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Melbourne, Australia : Blackwell Science Pty
    Nephrology 10 (2005), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: Recent in vitro studies have shown the synthesis of interleukin-6 (IL-6) in glomerular mesangial and epithelial cells, and suggested the involvement of IL-6 in mesangial proliferative glomerulonephritis. However, the expression site of IL-6 mRNA in renal tissue of IgA nephropathy (IgAN), the most common chronic mesangial proliferative glomerulonephritis, remains obscure. to localize IL-6 mRNA in renal biopsy specimens of IgAN, we used nonradioactive in situ hybridization (ISH) developed in our laboratory, sensitive in detecting individual cells positive for a specific mRNA. In some sections, periodic acid-Schiff staining was performed after ISH in order to identify the topographical relation between IL-6 mRNA positive cells and glomerular basement membrane and mesangial area. In situ hybridization for IL-6 mRNA and immunohistochemistry for CD3 and CD68, markers for lymphocytes and monocytes, respectively, were also performed on serial sections to examine the contribution of infiltrated mononuclear cells to cells positive for IL-6 mRNA in glomeruli. Glomerular resident cells, including glomerular mesangial and epithelial cells and cells of Bowman's capsule, as well as tubular epithelial cells and infiltrated mononuclear cells expressed IL-6 mRNA. We also compared the localization of IL-6 mRNA and protein and showed different distribution between the gene product and protein. the expression of IL-6 mRNA correlated with the degree of mesangial cell proliferation and tubulointerstitial changes. Our results indicate that IL-6 is synthesized in renal tissues of IgAN and suggest that the increased IL-6 expression may be important in the pathogenesis of IgAN.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Nephrology 3 (1997), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: Mesangial cell proliferation is a harbinger of glomerulosclerosis, leading to end-stage renal failure. It is, therefore, important to identify the factors that promote mesangial cell proliferation in order gain a better understanding of the progression of glomerular disease. A number of human and animal studies of glomerulonephritis have shown that infiltrating macrophages are prominent within mesangial proliferative lesions, suggesting that macrophages participate directly in the mesangial proliferative response. In vitro studies support a role for macrophages in mesangial cell proliferation. Macrophage interaction with mesangial cells through the action of leuckocyte adhesion molecules facilitates mesangial cell proliferation. This may be mediated by macrophage production of a number of mesangial cell growth factors or by modulating the mesangial matrix to promote mesangial cell growth. Mesangial cells may play an active role in this process, since mesangial cell production of chemoattractant molecules may be a key event in inducing macrophage recruitment into the injured mesangium. Taken together, these data suggest that macrophages and mesangial cells work in a co-operative fashion in the development of mesangioproliferative disease.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: Epidermal growth factor (EGF) is a potent mesangial cell and tubular epithelial cell mitogen. Based upon the novel finding that rat mesangial cells express EGF mRNA and protein in vitro, we investigated whether renal EGF production was involved in mesangial proliferation and concomitant tubular epithelial proliferation in rat anti-Thy-1 mesangial proliferative nephritis. During the period of mesangial proliferation in anti-Thy-1 nephritis (days 4–14) no EGF immunoreactive material was detected within the glomerulus. Epidermal growth factor-receptor (EGF-R) expression, which is strong on podocytes in normal glomeruli, was notably absent from focal areas of proliferating mesangial cells, suggesting that EGF available from the circulation was not involved in mesangial cell proliferation. Concomitant with the transient decline in creatinine clearance on day 8 of disease, there was mild tubular injury and a significant increase in cortical tubular proliferation as assessed by expression of the proliferating cell nuclear antigen (PCNA). Double immunohistochemistry staining found that the increased cortical tubular proliferation on day 8 occurred in EGF− tubules, but not EGF+ tubules. In contrast, there was an increase in proliferation of EGF+ tubules, but not EGF− tubules, on day 28. Renal EGF mRNA and protein expression was down-regulated over days 1-14, with a rebound in expression on day 28 which correlated with proliferation of EGF+ tubules. Tubular EGF-R expression, which is most clearly seen on EGF+ tubules in normal rat kidney, was unchanged over the disease course. the potential role of EGF in tubular proliferation in normal and diseased states is discussed. In summary, this study finds no evidence to implicate EGF in mesangial cell proliferation in rat anti-Thy-1 nephritis, even though mesangial cells can express EGF in vitro, and suggests that EGF may regulate proliferation of tubular epithelial cells in different stages of disease.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: Current experimental models of glomerulonephritis focus on the acute phases of renal injury. Models replicating the features of human glomerulonephritis, including hypertension, protein-uria, hyperlipidaemia, renal fibrosis and renal failure, are lacking. the aim of this experiment was to define a rat model of glomerulonephritis that replicates the features of progressive glomerulonephritis in humans. Passive accelerated antiglomerular basement membrane disease was induced in inbred Sprague-Dawley rats. Age-matched control rats received pre-immunisation, but were given saline rather than nephrotoxic serum. Groups of diseased rats (n=4–6) were killed at 4, 6 and 7 weeks, and tissues were extracted for histological assessment. Diseased rats developed renal failure over 7 weeks (91% reduction in creatinine clearance vs controls at week 7, P〈 0.001). Proteinuria reached a plateau from week 2 to week 7 (269.1 ± 107.9 mg/24h vs 1.00 ± 0.18 mg/mL for controls at week 7, P〈 0.001). Diseased rats became hyperlipidaemic (108% increase in cholesterol vs control, P〈0.05) and hypertensive (38% increase in systolic blood pressure vs controls, P〈0.001). Histology revealed progressive renal fibrosis and scarring, with fibrocellular crescent formation (93% of glomeruli by week 7), glomerulosclerosis and tubulointerstitial damage. α-Smooth muscle actin expression and interstitial matrix (collagen III) deposition increased progressively. Urinary transforming growth factor-β excretion was increased by over eightfold versus controls. This model of passive accelerated antiglomerular basement membrane disease simulates many clinical and pathological features of chronic giomerulonephritis in humans, and may provide a good model to test new therapies.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: Interleukin-10 (IL-10) has been recognized as a growth factor for rat mesangial cells in vitro; however, its role in mesangioproliferative glomerulonephritis is unknown. We studied the expression of IL-10 mRNA in the rat anti-Thy-1 model of mesangioproliferative glomerulonephritis (experiment 1) and, subsequently, the effects of blocking IL-10 during anti-Thy-1 nephritis using the IL-10 inhibitor, AS101 (experiment 2). In experiment 1, PCR analysis failed to detect IL-10 mRNA in normal rat kidney, however, a clear signal for IL-10 mRNA was evident on day 6 of anti-Thy-1 nephritis. In situ hybridization showed IL-10 mRNA expression in focal glomerular areas in anti-Thy-1 nephritis. Combined in situ hybridization and immunohistochemistry showed that glomerular IL-10 mRNA was expressed by both macrophages and mesangial cells. In experiment 2, treatment with AS101 significantly downregulated renal IL-10 gene expression, as demonstrated by semiquantitative PCR. However, the induction of glomerular hypercellularity, mesangial proliferation (PCNA+ cells), mesangial cell activation (α-SMA expression) and macrophage accumulation (ED1+ cells) seen in saline-treated anti-Thy-1 nephritis was unaffected by AS101 treatment. In conclusion, renal IL-10 gene expression is upregulated during pathological mesangial cell proliferation in rats with anti-Thy-1 nephritis. However, the inability of IL-10 suppression with AS101 to prevent anti-Thy-1 disease suggests that IL-10 is not essential for pathological mesangial cell proliferation.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Nephrology 3 (1997), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: Understanding the complex mechanisms involved in the induction and progression of glomerulonephritis requires a detailed analysis of the disease at the molecular level. This has become possible with the advent of antibody-based, and in particular, DNA-based techologies. This paper provides an overview of the methods of molecular analysis currently in use in the study of human glomerulonephritis. Although largely restricted to the research laboratories at present, these techniques of molecular analysis are now entering the mainstream of clinical diagnostic testing.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Melbourne, Australia : Blackwell Science Pty
    Nephrology 6 (2001), S. 0 
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY: This study evaluated the potential toxicity of Fast green and Lissamine green, the two dyes commonly used for visualizing tubular fluid flow in micropuncture studies. In both the in vitro perfused kidney and cultured tubular epithelial cells, Fast green exhibited a profound, dose-dependent toxicity. In contrast, Lissamine green was non-toxic. In conclusion, we recommend that Fast green not be used in micropuncture studies.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1440-1797
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary: The aim of this study was to examine the relationship of basic fibroblast growth factor (FGF-2) and its receptor (FGF-R) to tubular proliferation, interstitial fibrosis, glomerular cell proliferation and crescent formation in the development of anti glomerular basement membrane (GBM) glomerulonephrids in the rat. Using new microwave-based histochemistry techniques, weak constitutive expression of mRNA and protein for FGF-2 and FGF-R was evident in tubules and glomeruli of normal rat kidney. Double and triple staining with the proliferating cell nuclear antigen (PCNA) demonstrated that in disease there was focal up-regulation of FGF-2 and FGF-R mRNA and protein expression within proliferating tubules and fibroblast-like cells in areas of interstitial fibrosis. In contrast, tubules in non-inflamed areas of kidney showed no change in FGF-2 and FGF-R expression or cellular proliferation. In addition, many FGF-2+PCNA+ and FGF-R+PCNA+ cells, probably mesangial cells and podocytes, were evident within glomerular segmental proliferative lesions. of particular interest was the observation that many epithelial cells within cellular crescents, inculding proliferating (PCNA+) epithelial cells, strongly expressed both FGF-2 and FGF-R. Furthermore, there was strong FGF-2 and FGF-R expression by proliferating fibroblast-like cells within fibrocellular crescents suggesting that FGF-2 is involved in the formation and fibrotic progression of glomerular crescents. In conclusion, this study provides evidence that increased expression of FGF-2 and its receptor may participate in the proliferative/fibrotic response in progressive crescentic glomerulonephritis.
    Type of Medium: Electronic Resource
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