This proposal is to determine whether complement C3 is required for development and progressive expansion of kidney cysts induced by Pkd1 inactivation in mice. As the most common inherited disease, autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1 in 400 to 1000 live births. Approximately 85% of ADPKD results from mutation of PKD1, and the remaining 15% are from mutation of PKD2 gene. It is the progressive expansion and enlargement of numerous cysts that destroys normal kidney structure, impairs kidney function and causes clinical symptoms. There are also other factors that control onset and severity of ADPKD, especially aggressive progression of kidney cysts. Enlargement of kidney cysts is a slowly inflammatory process. Cytokines, growth factors and other inflammatory mediators are involved, but the exact mechanism and key mediators remain unclear. We found that complement C3 was elevated and activated in mouse and human AKPKD kidneys and cystic fluid. The local concentration and activation of complement C3 may be involved in development and expansion of kidney cysts. Based on the literature, complement C3 is one of the most highly induced genes in kidney tissue from a PKD mouse model. It is also present and highly expressed in cystic fluid and kidney tissue in human ADPKD. Thus, in order to further determine the essential role of complement C3 in development and aggressive expansion of kidney cysts in vivo, we will generate a double knockout mice (Mx1Cre+Pkd1flox/flox C3-/-) in which the C3 gene is deleted, and Pkd1 can also be conditionally knocked-out by crossing conditional ADPKD mice (Mx1Cre+Pkd1flox/flox) with C3 knockout mice (C3-/-). We will carry out several experiments to investigate how complement C3 promotes the aggressive cystic development, which includes the cell type producing local increased C3, the role of activated and cleaved fragments of C3 leading to focal inflammation and cystic expansion, the mechanism of C3 activation in cystic kidney (Aim 1). In mouse models, we expect that deletion of the complement C3 gene blocks or delays development and progression of kidney cysts induced by Pkd1 inactivation (Aim 2). Approximately one-half of ADPKD patients progress to chronic renal failure by age 60. Current treatment for this disease is dialysis or renal replacement therapy. Our proposed study would reveal a novel therapeutic strategy for this most common life-threatening genetic disease.

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Our proposed research is to investigate the essential role of complement C3 in development and progressive expansion of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD) mice. The outcome of this study would reveal a novel, feasible therapeutic strategy for this most common life-threatening genetic disease through inhibiting complement C3 activity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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Brigham and Women's Hospital
United States
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Wu, Yong; Xu, Jen X; El-Jouni, Wassim et al. (2016) G?12 is required for renal cystogenesis induced by Pkd1 inactivation. J Cell Sci 129:3675-3684
Xu, Jen X; Lu, Tzong-Shi; Li, Suyan et al. (2015) Polycystin-1 and G?12 regulate the cleavage of E-cadherin in kidney epithelial cells. Physiol Genomics 47:24-32