Recent work has shown that activation of the alternative pathway of complement is central to the pathogenesis of a large number of glomerular and tubulointerstitial renal diseases. It is not known, however, why the kidney is so frequently and uniquely vulnerable to alternative pathway-mediated injury. The central hypothesis of this grant is that the plasma protein factor H is critical for controlling alternativ pathway activation on the glomerular basement membrane and the surface of injured mesangial cells and tubular epithelial cells. Complement regulation within the kidney by factor H is disrupted by the local production of proteins that impair factor H function and by complement-activating microparticles shed by injured cells throughout the body. To test this hypothesis, the following specific aims will be pursued.
Aim 1) Determine which regulatory proteins control complement activation in the kidney. The working hypothesis for this aim is that factor H prevents spontaneous complement activation on the GBM and on injured mesangial and tubular epithelial cells. We will use in vitro and in vivo methods to determine which renal surfaces require factor H to prevent complement-mediated injury. We will use targeted complement inhibitors to restore factor H to sites of complement activation within the kidney.
Aim 2) Determine how the protein annexin A2 modulates complement regulation by factor H within the kidney. The working hypothesis for this aim is that annexin A2 expressed within the injured kidney blocks factor H function, thus permitting local activation of the alternative pathway. The experiments in this aim will utilize recombinant annexin A2, SiRNA, and mice with targeted deletion of the gene for annexin A2 in order to determine how annexin A2 promotes complement activation on the surface of cells of the kidney in vitro and in vivo.
Aim 3) Determine whether plasma microparticles impair complement regulation within the kidney. The working hypothesis of this aim is that microparticles shed from injured endothelial cells cause complement activation within the kidney. These experiments will utilize cyclosporine to generate endothelial microparticles and test whether they cause injury in factor H deficient mice. Cyclosporine-induced microparticles will be injected into factor H deficient mice to determine whether the microparticles directly increase alternative pathway activation and cause renal injury. Finally, we will test whether CR2-factor H, a targeted complement inhibitor, prevents cyclosporine-induced vascular and renal toxicity in factor H deficient mice. The approach outlined above is innovative because it challenges the current understanding of how factor H controls complement activation on tissues and it provides an explanation for why the kidney, among all of the organs, is so uniquely susceptible to alternative pathway-mediated injury. The studies in this grant are significant because they examine a process central to the pathogenesis of a wide range of renal diseases and provide new treatment strategies for these diseases.

Public Health Relevance

The proposed research is relevant to public health because activation of the complement system 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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK076690-07
Application #
8737226
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Renner, Brandon; Tong, Hua Hua; Laskowski, Jennifer et al. (2016) Annexin A2 Enhances Complement Activation by Inhibiting Factor H. J Immunol 196:1355-65
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Laskowski, Jennifer; Renner, Brandon; Le Quintrec, Moglie et al. (2016) Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury. Kidney Int 90:109-22
Stites, Erik; Le Quintrec, Moglie; Thurman, Joshua M (2015) The Complement System and Antibody-Mediated Transplant Rejection. J Immunol 195:5525-31
Thurman, Joshua M (2015) Complement in kidney disease: core curriculum 2015. Am J Kidney Dis 65:156-68
Thurman, Joshua M; Wong, Maria; Renner, Brandon et al. (2015) Complement Activation in Patients with Focal Segmental Glomerulosclerosis. PLoS One 10:e0136558

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