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  • INJURIES  (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 ; CELL ; Germany ; VOLUME ; TISSUE ; MICE ; INJURIES ; kidney ; MACROPHAGES ; MECHANISM ; REDUCTION ; renal ; CONTRAST ; INTERVENTION ; T cell ; T cells ; T-CELL ; T-CELLS ; FLOW ; fibroblasts ; TARGET ; LYMPHOCYTES ; WILD-TYPE ; RECRUITMENT ; leukocyte ; glomerulonephritis ; NEPHROPATHY ; FLOW-CYTOMETRY ; chemokine ; ANTAGONIST ; INJURY ; HOST-DEFENSE ; CHEMOKINE RECEPTOR ; fibrosis ; INFILTRATION ; fibroblast ; flow cytometry ; collagen ; CCR5 ; INTERSTITIAL FIBROSIS ; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA ; MICE LACKING ; OBSTRUCTION ; TRANSPLANT REJECTION
    Abstract: As chemokine receptor CCR1 and CCR5 expression on circulating leukocytes is thought to contribute to leukocyte recruitment during renal fibrosis, the authors examined the effects of unilateral ureteral obstruction (UUO) in mice deficient for CCR1 or CCR5. Analysis of UUO kidneys from CCR1-deficient mice revealed a reduction of interstitial macrophages and lymphocytes (35% and 55%, respectively) compared with wild-type controls. CCR1-deficient mice had reduced CCR5 mRNA levels in UUO kidneys, which correlated with a reduction of CCR5+ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-beta1 mRNA expression, interstitial volume, and collagen I deposits were all significantly reduced in CCR1-deficient mice. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. However, if treated with the CCR1 antagonist BX471, CCR5-deficient mice showed a similar reduction of renal leukocytes and fibrosis as CCR1-deficient mice. To determine the underlying mechanism labeled macrophages and T cells isolated from either wild-type, CCR1-deficient, or CCR5-deficient mice were injected into wild-type mice with UUO. Three hours later, renal cell recruitment was reduced for CCR1-deficient cells or cells pretreated with BX471 compared with CCR5-deficient or wild-type cells. Thus, CCR1 but not CCR5 is required for leukocyte recruitment and fibrosis after UUO in mice. Therefore, CCR1 is a promising target for therapeutic intervention in leukocyte-mediated fibrotic tissue injury, e.g. progressive renal fibrosis
    Type of Publication: Journal article published
    PubMed ID: 14747380
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