Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease

被引:75
作者
Ninichuk, V
Gross, O
Reichel, C
Khandoga, A
Pawar, RD
Ciubar, R
Segerer, S
Belemezova, E
Radomska, E
Luckow, B
de Lema, GP
Murphy, PM
Gao, JL
Henger, A
Kretzler, M
Horuk, R
Weber, M
Krombach, F
Schlöndorff, D
Anders, HJ
机构
[1] Univ Munich, Med Poliklin, Nephrol Ctr, D-80336 Munich, Germany
[2] Univ Munich, Inst Surg Res, D-80336 Munich, Germany
[3] Univ Cologne, Fac Med, Dept Internal Med 1, Cologne Gen Hosp,Merheim Med Ctr, Cologne, Germany
[4] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA
[5] Berlex Biosci, Dept Immunol, Richmond, CA USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2005年 / 16卷 / 04期
关键词
D O I
10.1681/ASN.2004100871
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Human Alport disease is caused by a lack of the alpha 3-, 4-, or 5-chain of type IV collagen (COL4A). Affected humans and COL4A3-deficient mice develop glomerulosclerosis and progressive renal fibrosis in the presence of interstitial macrophages, but their contribution to disease progression is under debate. This question was addressed by treating COL4A3-deficient mice with BX471, an antagonist of chemokine receptor 1 (CCR1) that is known to block interstitial leukocyte recruitment. Treatment with BX471 from weeks 6 to 10 of life improved survival of COL4A3-deficient mice, associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Cll5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. Thus, CCR1-mediated recruitment and local activation of macrophages contribute to disease progression in COL4A3-deficient mice. These data identify CCR1 as a potential therapeutic target for Alport disease or other progressive nephropathies associated with interstitial macrophage infiltrates.
引用
收藏
页码:977 / 985
页数:9
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