title: CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome.
abstract: BACKGROUND
  CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis.
  
  
  METHODS
  Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry.
  
  
  RESULTS
  At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and T lymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment.
  
  
  CONCLUSIONS
  Blockade of CCR1 substantially reduced interstitial leukocyte accumulation and the subsequent renal fibrosis in a murine model of nephrotic syndrome and FSGS. These findings support a role for CCR1 in interstitial leukocyte recruitment and suggest that CCR1 blockade might be a new therapeutic strategy in progressive nephropathies such as FSGS.
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik Innenstadt, Ludwig-Maximilians-University, Munich, Germany. volker.vielhauer@med.uni-muenchen.de
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
authors.forename: Elias
authors.initials: E
authors.lastname: Berning
authors.forename: Vaclav
authors.initials: V
authors.lastname: Eis
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.forename: Richard
authors.initials: R
authors.lastname: Horuk
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D018925:Chemokines / Q000378:metabolism; D004317:Doxorubicin; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C515301:Ccr1 protein, mouse; D018925:Chemokines; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D004317:Doxorubicin; C411885:BX 471