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      Chemokine Expression in the Obstructed Kidney

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          Chemokines are chemotactic cytokines that are important mediators of leukocyte extravasation and chemotaxis. Herein, we provide evidence that after 1 day of unilateral ureteral obstruction (UUO), the mouse obstructed kidney (OBK) expresses MCP-1 (monocyte chemoattractant protein-1), RANTES (Regulated on activation normal T-cell expressed and secreted) and IP-10 (interferon-γ-induced protein-10). In addition, by day 7, MIP-2 (macrophage inflammatory protein-2) expression is elevated in the obstructed kidneys compared to the contralateral control kidneys (CLK). After 7 days of obstruction, RANTES was the most abundant of the four chemokines detected in the OBK. In situ hybridization results indicate that several cellular compartments contribute to the expression of RANTES in the OBK. However, clearly cortical tubules within the OBK contribute substantially to the elevated expression of RANTES. These data support the contention that the cortical tubular epithelium plays a pivotal role in the inflammation associated with experimental hydronephrosis.

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          RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis

          The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
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            Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors.

            Recent studies indicate potential roles of monocyte chemotactic protein-1 (MCP-1) in recruitment of monocytes to sites of inflammation. However, their increased expression does not always correlate with monocyte influx, suggesting other possible biological activities for this member of the C-C chemokine family. In view of its potential role in regulating extracellular matrix expression in fibrotic disorders, the effects of MCP-1 on lung fibroblast collagen expression were evaluated. Isolated rat lung fibroblasts were treated with increasing doses of MCP-1 for variable periods of time and examined for effects on collagen synthesis and expression of procollagen alpha1(I) mRNA expression. The results show that MCP-1 was able to stimulate collagen expression in these cells in a dose-dependent manner but required over 24 h for significant elevation to occur. In view of this delayed time course, the possibility of mediation via endogenous transforming growth factor beta (TGFbeta) was tested by the ability of anti-TGFbeta antibody to inhibit this MCP-1 stimulation of collagen expression. Significant but incomplete inhibition by this antibody was observed. Pretreatment of the cells with antisense but not by sense or missense TGFbeta1 oligodeoxyribonucleotides caused essentially complete inhibition of this MCP-1 stimulatory effect. Furthermore, MCP-1 treatment was found to also stimulate TGFbeta secretion and mRNA expression, which was also abolished by pretreatment with antisense TGFbeta1 oligodeoxyribonucleotides. The kinetics of TGFbeta expression indicates that significant increase preceded that for collagen expression. Binding studies using 125I-labeled MCP-1 indicated the presence of specific and saturable binding sites with a dissociation constant consistent with the dose response curves for stimulation of fibroblast collagen synthesis and TGFbeta activity by MCP-1. These results taken together suggest that MCP-1 stimulates fibroblast collagen expression via specific receptors and endogenous up-regulation of TGFbeta expression. The latter then results in autocrine and/or juxtacrine stimulation of collagen gene expression.
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              Gene transfer of RANTES elicits autoimmune renal injury in MRL-Fas(1pr) mice.

              We report that the beta-chemokine RANTES, a chemoattractant for macrophages and T cells, is up-regulated in the MRL-Fas(1pr) kidney prior to injury, but not normal kidneys (MRL-++, C3H-++) and increases with progressive injury. Furthermore, we establish an association between RANTES expression in the kidney and renal damage using a gene transfer approach. Tubular epithelial cells genetically modified to secrete RANTES infused under the renal capsule incites interstitial nephritis in MRL-Fas(1pr), but not MRL-++ or C3H-++ mice. RANTES recruits predominantly macrophages (M phi) and CD4+ and CD8+ T cells. In contrast, gene transfer of CSF-1, another molecule up-regulated simultaneously with RANTES in MRL-Fas(1pr) kidneys, promotes the influx of M phi, CD4+ T cells and the unique double-negative (DN) T cells (CD4-, CD8-), which are prominent in diseased MRL-Fas(1pr) kidneys. Thus, RANTES and CSF-1 recruit distinct T cell populations into the MRL-Fas(1pr) kidney. In addition, delivery of RANTES and CSF-1 into the kidney of MRL-Fas(1pr) mice causes an additive increase in pathology. We suggest that the complementary recruitment of T cell populations by RANTES (CD4, CD8) and CSF-1 (CD4, DN) promotes autoimmune nephritis in MRL-Fas(1pr) mice.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                27 June 2001
                : 9
                : 4
                : 241-248
                Pennsylvania State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pa., USA
                52618 Exp Nephrol 2001;9:241–248
                © 2001 S. Karger AG, Basel

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                Figures: 5, References: 27, Pages: 8
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