Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease.
Human Alport disease is caused by a lack of the alpha3-, 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.
Ninichuk
Volha
V
Nephrological Center, Medical Policlinic, University of Munich, Germany.
Gross
Oliver
O
Reichel
Christoph
C
Khandoga
Andrej
A
Pawar
Rahul D
RD
Ciubar
Raluca
R
Segerer
Stephan
S
Belemezova
Emilia
E
Radomska
Ewa
E
Luckow
Bruno
B
Perez de Lema
Guillermo
G
Murphy
Philip M
PM
Gao
Ji-Liang
JL
Henger
Anna
A
Kretzler
Matthias
M
Horuk
Richard
R
Weber
Manfred
M
Krombach
Fritz
F
Schlöndorff
Detlef
D
Anders
Hans-Joachim
HJ
D000818:Animals; D001324:Autoantigens; D001808:Blood Vessels / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D024141:Collagen Type IV / Q000172:deficiency*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D036904:Leukocyte Rolling; D007962:Leukocytes; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors
D001324:Autoantigens; C515300:CCR1 protein, human; C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D024141:Collagen Type IV; D019402:Macrophage Inflammatory Proteins; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C057112:type IV collagen alpha3 chain; C411885:BX 471