Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis.
Monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and activating factor (MCAF)/CCL2, plays an important role in progressive organ fibrosis. It was hypothesized that MCP-1, through its cognate receptor, CCR2, regulates the pathogenesis and is therapeutically of importance for renal fibrosis. To achieve this goal, the therapeutic efficacy and efficiency in renal fibrosis induced by a unilateral ureteral obstruction nephropathy model in mice by the blockade of MCP-1/CCR2 signaling was studied. The delivery of N-terminal deletion mutant of the human MCP-1 gene, 7ND, into a skeletal muscle ameliorated renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-beta. Concomitantly, gene transfer of 7ND reduced the cell infiltration, most of which were CCR2-positive macrophages, followed by the decrease in MCP-1 expression in the diseased kidneys. These observations suggest that MCP-1 through CCR2 signaling is responsible for Mphi recruitment, which augments downstream events, resulting in renal fibrosis. Moreover, these findings imply that gene therapy against MCP-1/CCR2 signaling via the mutant gene transferred strategy may serve a beneficial therapeutic application for renal fibrosis.
Wada
Takashi
T
Department of Gastroenterology and Nephrology, Graduate School of Medical Science and Division of Blood Purification, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. twada@medf.m.kanazawa-u.ac.jp
Furuichi
Kengo
K
Sakai
Norihiko
N
Iwata
Yasunori
Y
Kitagawa
Kiyoki
K
Ishida
Yuko
Y
Kondo
Toshikazu
T
Hashimoto
Hiroyuki
H
Ishiwata
Yoshiro
Y
Mukaida
Naofumi
N
Tomosugi
Naohisa
N
Matsushima
Kouji
K
Egashira
Kensuke
K
Yokoyama
Hitoshi
H
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics*; D005355:Fibrosis; D015316:Genetic Therapy; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine