Uncontrolled activation of the alternative pathway of complement is central to the pathogenesis of multiple kidney diseases. Factor H is the main circulating regulator of the alternative pathway. It contains two binding regions, and mutations in one of these regions (referred to as Short Consensus Repeat 19-20, or SCR 19- 20) are associated with atypical hemolytic uremic syndrome. Thus, SCR 19-20 is believed to mediate binding of factor H to endothelial cells. Factor H defects are also associated with other kidney diseases, including C3 glomerulopathy, IgA nephropathy, and lupus nephritis. Furthermore, a group of proteins that antagonize factor H, called the factor H related proteins (FHRs), are associated with kidney disease. However, we do not yet have a unified understanding of why the different genetic variants in factor H or the FHRs cause distinct ultrastructural patterns of glomerular injury. It is also not known why the kidney is so uniquely vulnerable to injury in patients with systemic factor H mutations. Thus, greater understanding is needed regarding how these proteins interact with each other and with the kidney. In the last funding period of this grant we discovered that a protein produced within the kidney, annexin A2, blocks the other binding region of factor H, SCR 6-8. Overexpression of annexin A2 causes complement activation throughout the kidney, demonstrating that SCR 6-8 is critical for controlling complement activation on kidney surfaces. Interestingly, many disease-associated variants of the FHRs contain reduplications of this binding region. Based on these findings, the central hypothesis of this grant is that SCR 6-8 is critical for controlling alternative pathway activation on the glomerular basement (GBM), and SCR 19-20 is critical for controlling activation on endothelial cells. Mutations or proteins that interfere with these binding regions predispose patients to C3G and aHUS, respectively. To test this hypothesis, the following specific aims will be pursued.
Aim 1) Identify the molecular factors that control complement activation on renal surfaces. We will use in vitro systems to we will directly test whether SCR 6-8 mediates binding of factor H to the GBM and identify the binding ligands.
Aim 2) Test whether the FHRs and annexin A2 cause complement dysregulation in the kidney. We will use animal models to test the hypothesis that the FHRs and annexin A2 cause complement activation on specific surfaces within the kidney.
Aim 3) Develop novel therapies for blocking complement activation in the kidney. In this aim we will test whether new therapeutic strategies can specifically inhibit complement activation in the kidney while leaving other mechanisms of activation intact. This project is innovative because it provides a rational system for understanding how the numerous reported defects in factor H contribute to multiple different kidney diseases, and it provides an explanation for why the kidney is so uniquely susceptible to alternative pathway-mediated injury. The studies in this grant are significant because they test new treatment strategies for blocking complement activation specifically within the kidney.

Public Health Relevance

The proposed research is relevant to public heath because activation of the alternative pathway of complement contributes to renal injury in a wide range of renal diseases. Standard immunosuppressive drugs are not effective at preventing injury by the complement system. The therapeutic agents tested in these experiments may offer an important new approach to treating renal disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schulman, Ivonne Hernandez
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Tomlinson, Stephen; Thurman, Joshua M (2018) Tissue-targeted complement therapeutics. Mol Immunol 102:120-128
Goetz, Lindsey; Laskowski, Jennifer; Renner, Brandon et al. (2018) Complement factor H protects mice from ischemic acute kidney injury but is not critical for controlling complement activation by glomerular IgM. Eur J Immunol 48:791-802
Luo, Wentian; Olaru, Florina; Miner, Jeffrey H et al. (2018) Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. Front Immunol 9:1433
Klawitter, Jelena; Pennington, Alexander; Klawitter, Jost et al. (2017) Mitochondrial cyclophilin D ablation is associated with the activation of Akt/p70S6K pathway in the mouse kidney. Sci Rep 7:10540
Rubtsova, Kira; Rubtsov, Anatoly V; Thurman, Joshua M et al. (2017) B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J Clin Invest 127:1392-1404
Casiraghi, F; Azzollini, N; Todeschini, M et al. (2017) Complement Alternative Pathway Deficiency in Recipients Protects Kidney Allograft From Ischemia/Reperfusion Injury and Alloreactive T Cell Response. Am J Transplant 17:2312-2325
Thurman, Joshua M; Frazer-Abel, Ashley; Holers, V Michael (2017) The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases. Arthritis Rheumatol 69:2102-2113
Thurman, Joshua M (2017) Getting over our Immune-Complex - C5a receptor blockade is the answer. Cell Mol Immunol 14:319-320
Li, Dan; Zou, Lin; Feng, Yan et al. (2016) Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis. Crit Care Med 44:e289-99
Thurman, Joshua M; Nester, Carla M (2016) All Things Complement. Clin J Am Soc Nephrol 11:1856-1866

Showing the most recent 10 out of 53 publications