2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2004100871v1 16/4/977    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ninichuk, V. Articles by Anders, H.-J. Search for Related Content PubMed PubMed Citation Articles by Ninichuk, V. Articles by Anders, H.-J.

Delayed Chemokine Receptor 1 Blockade Prolongs Survival in Collagen 4A3–Deficient Mice with Alport Disease

Volha Ninichuk^*, Oliver Gross, Christoph Reichel, Andrej Khandoga, Rahul D. Pawar^*, Raluca Ciubar^*, Stephan Segerer^*, Emilia Belemezova^*, Ewa Radomska^*, Bruno Luckow^*, Guillermo Perez de Lema^*, Philip M. Murphy, Ji-Liang Gao, Anna Henger^*, Matthias Kretzler^*, Richard Horuk^||, Manfred Weber, Fritz Krombach, Detlef Schlöndorff^* and Hans-Joachim Anders^*

^* Nephrological Center, Medical Policlinic, University of Munich, Medical Faculty University of Cologne, Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, Cologne, and Institute for Surgical Research, University of Munich, Munich, Germany, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and ^|| Department of Immunology, Berlex Biosciences, Richmond, California

Address correspondence to: Dr. Hans-Joachim Anders, Medizinische Poliklinik LMU, Pettenkoferstrasse 8a, 80336 Munchen, Germany. Phone: +49-89-218075846; Fax: +49-89-218075860; hjanders{at}med.uni-muenchen.de

Received for publication October 21, 2004. Accepted for publication January 13, 2005.

Human Alport disease is caused by a lack of the 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.

This article has been cited by other articles:

				K. Furuichi, J.-L. Gao, R. Horuk, T. Wada, S. Kaneko, and P. M. Murphy Chemokine Receptor CCR1 Regulates Inflammatory Cell Infiltration after Renal Ischemia-Reperfusion Injury J. Immunol., December 15, 2008; 181(12): 8670 - 8676. [Abstract] [Full Text] [PDF]

				V. Ninichuk, S. Clauss, O. Kulkarni, H. Schmid, S. Segerer, E. Radomska, D. Eulberg, K. Buchner, N. Selve, S. Klussmann, et al. Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36-3'PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice Am. J. Pathol., March 1, 2008; 172(3): 628 - 637. [Abstract] [Full Text] [PDF]

				P. Boor, K. Sebekova, T. Ostendorf, and J. Floege Treatment targets in renal fibrosis Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3391 - 3407. [Full Text] [PDF]

				B. Lange-Sperandio, A. Trautmann, O. Eickelberg, A. Jayachandran, S. Oberle, F. Schmidutz, B. Rodenbeck, M. Homme, R. Horuk, and F. Schaefer Leukocytes Induce Epithelial to Mesenchymal Transition after Unilateral Ureteral Obstruction in Neonatal Mice Am. J. Pathol., September 1, 2007; 171(3): 861 - 871. [Abstract] [Full Text] [PDF]

				V. Mayer, K. L. Hudkins, F. Heller, H. Schmid, M. Kretzler, U. Brandt, H.-J. Anders, H. Regele, P. J. Nelson, C. E. Alpers, et al. Expression of the chemokine receptor CCR1 in human renal allografts Nephrol. Dial. Transplant., June 1, 2007; 22(6): 1720 - 1729. [Abstract] [Full Text] [PDF]

				V. Ninichuk, A. G. Khandoga, S. Segerer, P. Loetscher, A. Schlapbach, L. Revesz, R. Feifel, A. Khandoga, F. Krombach, P. J. Nelson, et al. The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice Am. J. Pathol., April 1, 2007; 170(4): 1267 - 1276. [Abstract] [Full Text] [PDF]

				C. A. Reichel, A. Khandoga, H.-J. Anders, D. Schlondorff, B. Luckow, and F. Krombach Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutrophil migration to postischemic tissue J. Leukoc. Biol., January 1, 2006; 79(1): 114 - 122. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673