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Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis.

ABSTRACT: Glomerular monocyte/macrophage (Mo/M phi) infiltrates play a role in many forms of glomerulonephritis (GN), and the intensity of Mo/M phi trafficking correlates with the loss of renal function and histological damage. We analyzed the functional role of macrophage-derived chemokine (MDC), a potent mononuclear cell chemoattractant, during the progression of anti-glomerular basement membrane (GBM) antibody (Ab) GN, a model of crescentic GN in the WKY rat, and whether the effects of MDC were dependent on its receptor CCR4. MDC mRNA and protein expression were markedly induced in nephritic glomeruli throughout the disease. Blocking the function of MDC did not affect the developing of the disease from days 2 to 7, but it dramatically blocked M omicron/M phi infiltration in the glomeruli, prevented crescent formation, and reversed renal function impairment during days 7 to 14 of the anti-GBM GN. In this study, we also found that MDC activity on M omicron/M phi in this GN was at least partly dependent on a new variant of CCR4. These results suggest that MDC is critically involved in the development of anti-GBM GN from acute glomerular injury to irreversible tissue damage. In addition, an antagonist to MDC may represent a prime drug target for therapeutic application to intervene in the progression of anti-GBM GN and in other M omicron/M phi-dominant GN.

SUBMITTER: Garcia GE

PROVIDER: S-EPMC1851244 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis.

Garcia Gabriela E GE Xia Yiyang Y Harrison Jeffrey J Wilson Curtis B CB Johnson Richard J RJ Bacon Kevin B KB Feng Lili L

The American journal of pathology 20030401 4

Glomerular monocyte/macrophage (Mo/M phi) infiltrates play a role in many forms of glomerulonephritis (GN), and the intensity of Mo/M phi trafficking correlates with the loss of renal function and histological damage. We analyzed the functional role of macrophage-derived chemokine (MDC), a potent mononuclear cell chemoattractant, during the progression of anti-glomerular basement membrane (GBM) antibody (Ab) GN, a model of crescentic GN in the WKY rat, and whether the effects of MDC were depende ...[more]

PMID: 12651599

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Project description:BackgroundFunction and efficiency of a transcription factor (TF) are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis (Crgn) where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto (WKY) strain.ResultsTo evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains (WKY and WKY.LCrgn2) that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD/Jun and JunD/ATF complexes (i.e., AP1 complex), which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide (LPS) stimulation we found that 2.4 fold more JunD/ATF-target genes were up-regulated as compared with JunD/Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response (P = 6.9 × 10⁻⁴) and antigen processing and presentation functions (P = 2.4 × 10⁻⁵), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF.ConclusionsIn summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis.

Dataset Information

Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis.

Publications

Mononuclear cell-infiltrate inhibition by blocking macrophage-derived chemokine results in attenuation of developing crescentic glomerulonephritis.

Similar Datasets

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