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Published on: October 26, 2020
Blockade of CCR2 ameliorates progressive fibrosis in kidney
Kiyoki Kitagawa1, Takashi Wada, Kengo Furuichi
1Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Abstract:
Fibrosis is a hallmark of progressive organ diseases. Monocyte chemoattractant protein (MCP)-1, also termed as macrophage chemotactic and activating factor (MCAF/CCL2) and its receptor, CCR2 are presumed to contribute to progressive fibrosis. However, the therapeutic efficacy of MCP-1/CCR2 blockade in progressive fibrosis remains to be investigated. We hypothesized that blockade of CCR2 may lead to the improvement of fibrosis. To achieve this goal, we investigated renal interstitial fibrosis induced by a unilateral ureteral obstruction in CCR2 gene-targeted mice and mice treated with propagermanium or RS-504393, CCR2 inhibitors. Cell infiltrations, most of which were F4/80-positive, were reduced in CCR2 knockout mice. In addition, dual staining revealed that CCR2-positive cells were mainly F4/80-positive macrophages. Importantly, CCR2 blockade reduced renal interstitial fibrosis relative to wild-type mice. Concomitantly, renal transcripts and protein of MCP-1, transforming growth factor-beta, and type I collagen were decreased in CCR2-null mice. Further, this CCR2-dependent loop for renal fibrosis was confirmed by treatment with CCR2 antagonists in a unilateral ureteral obstruction model. These findings suggest that the therapeutic strategy of blocking CCR2 may prove beneficial for progressive fibrosis via the decrease in infiltration and activation of macrophages in the diseased kidneys.
Insights
Blocking the CCR2 receptor may improve organ fibrosis by reducing macrophage infiltration and activation. This study investigated CCR2 inhibition as a therapeutic strategy for progressive fibrotic diseases.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Fibrosis is a key feature of progressive organ damage.
- Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 are implicated in fibrosis progression.
- The therapeutic potential of blocking MCP-1/CCR2 in fibrosis is not fully understood.
Purpose of the Study:
- To investigate the therapeutic efficacy of CCR2 blockade in mitigating renal interstitial fibrosis.
- To determine if blocking CCR2 can reduce macrophage infiltration and activation in fibrotic kidneys.
Main Methods:
- Utilized CCR2 knockout mice and wild-type mice subjected to unilateral ureteral obstruction (UUO).
- Administered CCR2 inhibitors (propagermanium, RS-504393) to mice with UUO-induced renal fibrosis.
- Assessed cell infiltration (F4/80 staining), macrophage markers, and fibrotic markers (MCP-1, TGF-β, collagen I).
Main Results:
- CCR2 knockout mice exhibited reduced F4/80-positive cell infiltration compared to wild-type controls.
- CCR2 blockade significantly decreased renal interstitial fibrosis in UUO models.
- Blocking CCR2 led to decreased expression of MCP-1, TGF-β, and type I collagen in kidneys.
Conclusions:
- CCR2 plays a crucial role in mediating renal interstitial fibrosis.
- Therapeutic strategies targeting CCR2 blockade show promise for treating progressive fibrotic diseases.
- Inhibition of CCR2 may reduce fibrosis by limiting macrophage infiltration and activation in diseased organs.
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