Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice.
Slowly progressive renal injury is the major cause for ESRD. The model of progressive immune complex glomerulonephritis in autoimmune MRL(lpr/lpr) mice was used to evaluate whether chemokine receptor CCR1 blockade late in the disease course can affect progression to renal failure. Mice were treated with subcutaneous injections of either vehicle or BX471, a nonpeptide CCR1 antagonist, three times a day from week 20 to 24 of age [corrected]. BX471 improved blood urea nitrogen levels (BX471, 35.1 +/- 5.3; vehicle, 73.1 +/- 39.6 mg/dl; P < 0.05) and reduced the amount of ERHR-3 macrophages, CD3 lymphocytes, Ki-67 positive proliferating cells, and ssDNA positive apoptotic cells in the interstitium but not in glomeruli. Cell transfer studies with fluorescence-labeled T cells that were pretreated with either vehicle or BX471 showed that BX471 blocks macrophage and T cell recruitment to the renal interstitium of MRL(lpr/lpr) mice. This was associated with reduced renal expression of CC chemokines CCL2, CCL3, CCL4, and CCL5 and the chemokine receptors CCR1, CCR2, and CCR5. Furthermore, BX471 reduced the extent of interstitial fibrosis as evaluated by interstitial smooth muscle actin expression and collagen I deposits, as well as mRNA expression for collagen I and TGF-beta. BX471 did not affect serum DNA autoantibodies, proteinuria, or markers of glomerular injury in MRL(lpr/lpr) mice. This is the first evidence that, in advanced chronic renal injury, blockade of CCR1 can halt disease progression and improve renal function by selective inhibition of interstitial leukocyte recruitment and fibrosis.
Anders
Hans-Joachim
HJ
Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany. hjanders@med.uni-muenchen.de
Belemezova
Emilia
E
Eis
Vaclav
V
Segerer
Stephan
S
Vielhauer
Volker
V
Perez de Lema
Guillermo
G
Kretzler
Matthias
M
Cohen
Clemens D
CD
Frink
Michael
M
Horuk
Richard
R
Hudkins
Kelly L
KL
Alpers
Charles E
CE
Mampaso
Francisco
F
Schlöndorff
Detlef
D
D000818:Animals; D001323:Autoantibodies / Q000737:chemistry; D001806:Blood Urea Nitrogen; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis; D005921:Glomerulonephritis / Q000378:metabolism; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D008181:Lupus Nephritis / Q000188:drug therapy*; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008856:Microscopy, Fluorescence; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D001323:Autoantibodies; D017252:CD3 Complex; C515301:Ccr1 protein, mouse; D018925:Chemokines; D004277:DNA, Single-Stranded; D019394:Ki-67 Antigen; D010671:Phenylurea Compounds; D010880:Piperidines; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D004247:DNA; C411885:BX 471