Complement is a part of innate immunity and plays a key role in host defense. However, if not properly regulated, activated complement can cause inflammatory injury. Recent works have identified complement as a major pathogenic pathway in many human immunological and inflammatory diseases. Among them, dense deposit disease (DDD) is a rare kidney disease caused by dysregulation of the alternative pathway (AP) of complement activation. DDD is characterized by the presence of electron- dense deposits within the glomerular basement membrane of the kidney. Known also as membranoproliferative glomerulonephritis type II (MPGN type II), DDD belongs to the recently introduced pathological entity called C3 glomerulopathy whose definition is glomerular pathology characterized by C3 accumulation with no or limited immunoglobulin deposition. Approximately 10% of DDD patients also develop vision problems with dense deposits underneath retinal pigment epithelial cells that resemble drusen deposits in the eyes of age-related macular degeneration patients. Prognosis of DDD is poor since current treatments are largely nonspecific and about 50% patients eventually progress to end stage renal failure. Mechanistic and therapeutic studies of human DDD have been hampered by the lack of appropriate animal models. We have recently generated a robust mouse model of DDD displaying both kidney and retinal pathologies. The objective of this application is to use this novel mouse model to investigate the pathogenic mechanisms of complement-mediated kidney and retinal injury in DDD and to test the activity of various anti-complement agents in preventing or reversing the kidney and eye pathologies. Our long term goal is to better understand how dysregulated AP complement leads to DDD and other complement-mediated inflammatory disorders and to provide proof of principle for developing novel anti-complement therapies for such human diseases.

Public Health Relevance

This project uses a mouse model to study what causes and how to treat a rare human disease called dense deposit disease (DDD). Patients with DDD often develop kidney failure and vision loss and currently no treatment is available. The proposed studies will help the development of highly specific and effective drugs for these patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI085596-07
Application #
9172227
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Nasseri, M Faraz
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zhang, Congcong; Li, Yulin; Wang, Chunxiao et al. (2014) Complement 5a receptor mediates angiotensin II-induced cardiac inflammation and remodeling. Arterioscler Thromb Vasc Biol 34:1240-8
Miao, Jing; Lesher, Allison M; Miwa, Takashi et al. (2014) Tissue-specific deletion of Crry from mouse proximal tubular epithelial cells increases susceptibility to renal ischemia-reperfusion injury. Kidney Int 86:726-37
Lesher, Allison M; Zhou, Lin; Kimura, Yuko et al. (2013) Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis. J Am Soc Nephrol 24:53-65
Miwa, Takashi; Sato, Sayaka; Gullipalli, Damodar et al. (2013) Blocking properdin, the alternative pathway, and anaphylatoxin receptors ameliorates renal ischemia-reperfusion injury in decay-accelerating factor and CD59 double-knockout mice. J Immunol 190:3552-9
Lesher, Allison M; Nilsson, Bo; Song, Wen-Chao (2013) Properdin in complement activation and tissue injury. Mol Immunol 56:191-8
Ruseva, Marieta M; Vernon, Katherine A; Lesher, Allison M et al. (2013) Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency. J Am Soc Nephrol 24:43-52
Gauvreau, Danny; Roy, Christian; Tom, Fun-Qun et al. (2012) A new effector of lipid metabolism: complement factor properdin. Mol Immunol 51:73-81
Song, Wen-Chao (2012) Crosstalk between complement and toll-like receptors. Toxicol Pathol 40:174-82
Miwa, Takashi; Zhou, Lin; Maldonado, Michael A et al. (2012) Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice. J Immunol 189:5434-41

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