# Complement-mediated injury of the kidney: New mechanisms and novel therapies

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $348,305

## Abstract

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 susce...

## Key facts

- **NIH application ID:** 10166831
- **Project number:** 5R01DK076690-14
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua M Thurman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,305
- **Award type:** 5
- **Project period:** 2008-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166831

## Citation

> US National Institutes of Health, RePORTER application 10166831, Complement-mediated injury of the kidney: New mechanisms and novel therapies (5R01DK076690-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10166831. Licensed CC0.

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