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Abstract: SA-PO635

Modeling C3 Glomerulopathies on Extracellular Matrix Surface

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Pisarenka, Sofiya, The University of Iowa, Iowa City, Iowa, United States
  • Zhang, Yuzhou, The University of Iowa, Iowa City, Iowa, United States
  • Smith, Richard J., The University of Iowa, Iowa City, Iowa, United States

Group or Team Name

  • MORL
Background

C3 glomerulopathies (C3G) are ultra-rare complement mediated diseases that lead to end-stage renal failure within 10 years of diagnosis in ~50% of patients. The underlying cause of C3G is dysregulation of the alternative pathway (AP) of complement in the fluid phase (i.e. circulation) and/or the renal glomerulus. The latter is comprised of glomerular fenestrae, which are blanketed by extracellular matrix (ECM) and depend on circulating regulators for complement control in this microenvironment. Here we present an in vitro model of ECM-specific AP C3 convertase activation and regulation.

Methods

A human ECM substitute (MaxGel) was used as a base upon which AP C3 convertase was reconstituted. Convertase activity and regulation was validated using inhibiting (Factor H) and stabilizing (Properdin) regulators of complement activation. Once validated, we used this model to assess the effect of C3 Nephritic factors (C3Nefs) on C3 convertase activity.

Results

AP C3 convertase forms and decays on MaxGel in the expected manner; negative and positive regulation by FH and FP, respectively, was also observed. In the presence of IgGs derived from C3G patients positive for C3Nefs, the rate of decay of C3 convertase was significantly decreased when compared to C3 convertase alone, normal human serum IgGs, and IgGs derived from C3G patients negative for C3Nefs.

Conclusion

We conclude that this model of the glycomatrix offers a reliable and replicable method of evaluating various drivers of C3G in an environment similar to that of the glycomatrix. Further, we show that patient-specific assessment of C3 convertase activity and regulation is possible, thus offering an improved understanding of the effect of different disease factors on C3G pathogenesis.

Figure 1: C3 convertase decay decreases in presence of IgGs from C3G patients positive for C3Nefs.