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  • INJECTION  (2)
  • 1
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; MODEL ; SUPPORT ; VOLUME ; TISSUE ; MICE ; INJURIES ; LIGAND ; NEPHRITIS ; RANTES ; kidney ; MACROPHAGES ; murine ; MARKER ; renal ; RAT ; CONTRAST ; INJECTION ; fibroblasts ; treatment ; IDENTIFICATION ; LESIONS ; immunohistochemistry ; MARKERS ; LIGANDS ; RECRUITMENT ; leukocyte ; STRATEGIES ; intravenous ; NEPHROPATHY ; chemokine ; INITIATION ; ANTAGONIST ; inflammation ; INJURY ; FOCAL SEGMENTAL GLOMERULOSCLEROSIS ; CHEMOKINE RECEPTOR ; fibrosis ; PERSISTENT ; INFILTRATION ; MURINE MODEL ; chemokines ; OBSTRUCTIVE NEPHROPATHY ; progressive nephropathy ; receptor blockade ; RENAL-DISEASE
    Abstract: Background. CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis. Methods. Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry. Results. At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and Tlymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment. Conclusion. Blockade of CCR1 substantially reduced interstitial leukocyte accumulation and the subsequent renal fibrosis in a murine model of nephrotic syndrome and FSGS. These findings support a role for CCR1 in interstitial leukocyte recruitment and suggest that CCR1 blockade might be a new therapeutic strategy in progressive nephropathies such as FSGS
    Type of Publication: Journal article published
    PubMed ID: 15569315
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; MICE ; ACTIVATION ; DNA ; INFECTION ; kidney ; MECHANISM ; murine ; SERA ; renal ; CONTRAST ; DENDRITIC CELLS ; mechanisms ; INJECTION ; antibodies ; PROGRESSION ; ESCHERICHIA-COLI ; EPITHELIAL-CELLS ; VIRAL-INFECTION ; AUTOIMMUNITY ; BACTERIAL CPG-DNA ; CHEMOKINE RECEPTOR ; chemokines,autoimmune diseases,kidney,lupus,immunity ; IMMUNE-COMPLEX GLOMERULONEPHRITIS ; IMMUNIZATION ; NZB/NZW MICE ; SYSTEMIC-LUPUS-ERYTHEMATOSUS
    Abstract: How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL1pr/1pr mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL1pr/1pr mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL1pr/1pr mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG(2a) isotype in MRL1pr/1pr mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis
    Type of Publication: Journal article published
    PubMed ID: 14734643
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