A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation

Anders, Hans‐Joachim; Vielhauer, Volker; Frink, Michael; Linde, Yvonne; Cohen, Clemens D.; Blattner, Simone M.; Kretzler, Matthias; Strutz, Frank; Mack, Matthias; Gröne, Hermann–Josef; Onuffer, James; Horuk, Richard; Nelson, Peter J.; Schlöndorff, Detlef

doi:10.1172/jci200214040

Cited by 62 publications

(85 citation statements)

References 21 publications

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“…Statistical analysis of treatment groups was performed using analysis of variance. Tubular damage and interstitial volume were assessed as previously described 25,26 with modifications. In brief, ϫ20 images were taken from sections stained with Trichrome-Masson.…”

Section: Quantitation Of Sma Immunostaining Tubular Damage and Intementioning

confidence: 99%

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

173

132

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The transforming growth factor (TGF)-␤-inducible integrin ␣v␤6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-␤. Herein , we show that ␣v␤6 is overexpressed in human kidney epithelium in membranous glomerulonephritis , diabetes mellitus , IgA nephropathy , Goodpasture's syndrome , and Alport syndrome renal epithelium. To assess the potential regulatory role of ␣v␤6 in renal disease , we studied the effects of functionblocking ␣v␤6 monoclonal antibodies (mAbs) and genetic ablation of the ␤6 subunit on kidney fibrosis in Col4A3 ؊/؊ mice , a mouse model of Alport syndrome. Expression of ␣v␤6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with ␣v␤6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in ␤6-deficient Alport mice. Transcript profiling of kidney tissues showed that ␣v␤6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-␤ RII treatment , suggesting shared regulatory functions of ␣v␤6 and TGF-␤. These findings demonstrate that ␣v␤6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

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Section: Quantitation Of Sma Immunostaining Tubular Damage and Intementioning

confidence: 99%

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

173

132

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“…For all experiments, 8-to 12-wk-old animals were used. One group of CCR5-deficient mice were treated with the CCR1 antagonist BX471 (50 mg/kg body wt, thrice daily, subcutaneously) from day 0 to day 10 as described (9). Sex-matched and age-matched controls were obtained from Charles River, Sulzfeld, Germany.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Positive cells were counted per hpf omitting positive cells in glomerular fields. Quantitation of the interstitial volume (I Vol ), interstitial collagen deposition (I col ), and tubular dilatation (I Tdil ) was performed as described previously (9).…”

Section: Morphologic Evaluationmentioning

confidence: 99%

“…F4/80-positive macrophages and CD8-positive T cells were obtained from wild-type mice as described above. mRNA of isolated cells was prepared by standard methods as described (9) …”

Section: Isolation Of Cells For Real-time Rt-pcrmentioning

confidence: 99%

“…Evidence for the role of CCR1 in renal disease comes from a study that showed that the CCR1 antagonist BX471 was similar to cyclosporin in its ability to prevent renal allograft rejection and to improve survival in rabbits (8). Furthermore, we have recently shown that BX471 reduced leukocyte accumulation and renal fibrosis after UUO in mice (9). However, when CCR1-deficient mice were injected with nephrotoxic serum they showed enhanced glomerular T cell infiltration, crescent formation, and proteinuria in association with an enhanced Th1-response, indicating CCR1 is also involved in the regulation of systemic immune responses (10).…”

mentioning

confidence: 99%

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Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Eis¹,

Luckow²,

Vielhauer³

et al. 2004

Journal of the American Society of Nephrology

121

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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 CCR5ϩ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-␤1 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.

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Family history of cancer predicts Papanicolaou screening behavior for African American and white women

Williams

Reiter

Mabiso

et al. 2008

Cancer

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Objective To examine the role of an interaction between fibroblasts and mononuclear infiltrates through CD40–CD154 engagement in the development of tissue fibrosis. Methods Cultured dermal fibroblasts derived from healthy skin were induced to express CD40 by adenoviral gene transfer, stimulated with soluble CD154, and evaluated for proliferation, gene expression, and protein expression in vitro. The skin of mice with bleomycin‐induced skin sclerosis, a model for systemic sclerosis (SSc), was assessed for CD40 and CD154 expression, in vivo fibroblast proliferation, and the expression of specific genes. The effects of an anti‐CD154 monoclonal antibody on bleomycin‐induced skin sclerosis were also examined. Results Upon stimulation with soluble CD154, cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up‐regulation of the genes for intercellular adhesion molecule 1, interleukin‐6 (IL‐6), IL‐8, monocyte chemoattractant protein 1 (MCP‐1), and RANTES, as well as up‐regulation of their proteins. In the skin from bleomycin‐treated mice, dermal fibroblasts expressed CD40, and mast cells and CD4+ T cells expressed CD154. Electron microscopic analysis revealed fibroblasts attached to mast cells and T cells with primitive contacts. The proliferation of fibroblasts and the up‐regulated MCP‐1 gene expression preceded thickening of the dermis. Finally, the anti‐CD154 antibody inhibited the bleomycin‐induced skin sclerosis by suppressing fibroblast proliferation and down‐regulating MCP‐1 expression. Conclusion The interaction between fibroblasts and mast cells or T cells through CD40–CD154 signaling is critical for fibroblast activation early in the course of fibrosis. Blockade of the CD40–CD154 signal may be a novel therapeutic strategy for human fibrotic diseases, such as SSc.

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A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation

Cited by 62 publications

References 21 publications

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Chemokine Receptor CCR1 But Not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction

Family history of cancer predicts Papanicolaou screening behavior for African American and white women

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