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Complement C5 Mediates Experimental Tubulointerstitial Fibrosis

Peter Boor^*,, Andrzej Konieczny^*, Luigi Villa^*, Anna-Lisa Schult^*, Eva Bücher^*, Song Rong^*, Uta Kunter^*, Claudia R.C. van Roeyen^*, Thomas Polakowski, Heiko Hawlisch, Sonja Hillebrandt, Frank Lammert, Frank Eitner^*, Jürgen Floege^* and Tammo Ostendorf^*

^* Division of Nephrology, Rheinische-Westfälische Technische Hochschule, University of Aachen, Aachen, Germany; Department of Clinical and Experimental Pharmacotherapy, Research Base of Slovak Medical University, Bratislava, Slovakia; Jerini AG, Berlin, Germany; and Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany

Address correspondence to: Dr. Tammo Ostendorf, Division of Nephrology and Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. Phone: +49-241-8089424; Fax: +49-241-8082446; E-mail: tostendorf{at}ukaachen.de

Received for publication December 12, 2006. Accepted for publication February 7, 2007.

Renal fibrosis is the final common pathway of most progressive renal diseases. C5 was recently identified as a risk factor for liver fibrosis. This study investigated the role of C5 in the development of renal tubulointerstitial fibrosis by (1) induction of renal fibrosis in wild-type and C5^–/– mice by unilateral ureteral ligation (UUO) and (2) investigation of the effects of a C5a receptor antagonist (C5aRA) in UUO. In C5^–/– mice, when compared with wild-type controls, markers of renal fibrosis (Sirius Red, type I collagen, fibronectin, -smooth muscle actin, vimentin, and infiltrating macrophages) were significantly reduced on day 5 of UUO. On day 10, fibronectin mRNA and protein expression were still reduced in the C5^–/– mice. Cortical mRNA of all PDGF isoforms and of TGF-₁ (i.e., central mediators of renal disease) were significantly reduced in C5^–/– mice when compared with controls. Renal tubular cell expression of the C5aR was sparse in normal cortex but markedly upregulated after UUO. Treatment of wild-type UUO mice with C5aRA also led to a significant reduction of cortical Sirius Red staining, fibronectin protein expression, and PDGF-B mRNA expression on day 5. Neither genetic C5 deficiency nor C5aRA treatment caused any histologic changes in the nonobstructed kidneys. In cultured murine cortical tubular cells, C5a stimulated production of TGF-₁, and this was inhibited by C5aRA. Using a combined genetic and pharmacologic approach, C5, in particular C5a, is identified as a novel profibrotic factor in renal disease and as a potential new therapeutic target.

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