A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation.
The expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and progressive renal fibrosis after unilateral ureter obstruction (UUO). We hypothesized that blocking the chemokine receptor CCR1 using the nonpeptide antagonist BX471 could reduce leukocyte infiltration and renal fibrosis after UUO. UUO kidneys from BX471-treated mice (day 0-10 and day 6-10) revealed a 40-60% reduction of interstitial macrophage and lymphocyte infiltrate compared with controls. Treated mice also showed a marked reduction of CCR1 and CCR5 mRNA levels, and FACS analysis showed a comparable reduction of CD8+/CCR5+ T cells. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, were all significantly reduced by BX471-treatment compared with vehicle controls. By contrast treatment was ineffective when the drug was supplied only from days 0 to 5. In summary, blockade of CCR1 substantially reduces cell accumulation and renal fibrosis after UUO. Most interestingly, late onset of treatment is also effective. We therefore conclude that CCR1 blockade may represent a new therapeutic strategy for reducing cellular infiltration and renal fibrosis as major factors in the progression to end-stage renal failure.
Anders
Hans-Joachim
HJ
Nephrological Center, Medizinische Poliklinik, Innenstadt, Universität München, München, Germany. hjanders@clinbio.med.unimuenchen.de
Vielhauer
Volker
V
Frink
Michael
M
Linde
Yvonne
Y
Cohen
Clemens D
CD
Blattner
Simone M
SM
Kretzler
Matthias
M
Strutz
Frank
F
Mack
Matthias
M
Gröne
Hermann-Josef
HJ
Onuffer
James
J
Horuk
Richard
R
Nelson
Peter J
PJ
Schlöndorff
Detlef
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D007684:Kidney Tubules / Q000293:injuries; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008026:Ligation / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014513:Ureter / Q000503:physiopathology
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C411885:BX 471; D002118:Calcium