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Treatment with an Inhibitory Monoclonal Antibody to Mouse Factor B Protects Mice from Induction of Apoptosis and Renal Ischemia/Reperfusion Injury

Joshua M. Thurman^*, Pamela A. Royer^*, Danica Ljubanovic, Belda Dursun^*, Amanda M. Lenderink^*, Charles L. Edelstein^* and V. Michael Holers^*

^* Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Department of Pathology, University Hospital Dubrava, Zagreb, Croatia

Address correspondence to: Dr. Joshua M. Thurman, University of Colorado Health Sciences Center, Division of Renal Diseases and Hypertension, 4200 E. 9th Avenue, B-115, Denver, CO 80262. Phone: 303-315-0171; Fax: 303-315-5540; joshua.thurman{at}uchsc.edu

Received for publication July 8, 2005. Accepted for publication December 10, 2005.

Complement activation in the kidney after ischemia/reperfusion (I/R) seems to occur primarily via the alternative complement pathway. The ability of an inhibitory mAb to mouse factor B, a necessary component of the alternative pathway, to protect mice from ischemic acute renal failure was tested. Treatment with the mAb prevented the deposition of C3b on the tubular epithelium and the generation of systemic C3a after renal I/R. Treated mice had significantly lower increases in serum urea nitrogen and developed significantly less morphologic injury of the kidney after I/R. For gaining insight into potential mechanisms of protection, the activity of caspases within the kidney also was measured, and it was found that caspases-2, -3, and -9 increased in a complement-dependent manner after renal I/R. Apoptotic cells were detected by terminal deoxynucleotidyl transferase catalyzed labeling of DNA fragments, and mice in which the alternative pathway was inhibited demonstrated significantly less apoptosis than control mice. Thus, use of an inhibitory mAb to mouse factor B effectively prevented activation of complement in the kidney after I/R and protected the mice from necrotic and apoptotic injury of the tubules.

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