Blockade of CCR2 ameliorates progressive fibrosis in kidney.
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.
Kitagawa
Kiyoki
K
Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Wada
Takashi
T
Furuichi
Kengo
K
Hashimoto
Hiroyuki
H
Ishiwata
Yoshiro
Y
Asano
Masahide
M
Takeya
Motohiro
M
Kuziel
William A
WA
Matsushima
Kouji
K
Mukaida
Naofumi
N
Yokoyama
Hitoshi
H
D000818:Animals; D000943:Antigens, Differentiation / Q000187:drug effects / Q000378:metabolism; D017252:CD3 Complex / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005857:Germanium; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000627:therapeutic use; D011422:Propionates; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
D000943:Antigens, Differentiation; D017252:CD3 Complex; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D009942:Organometallic Compounds; D011422:Propionates; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; C036763:monocyte-macrophage differentiation antigen; D005857:Germanium; C066750:propagermanium