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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $468,016

## Abstract

The alternative pathway of complement contributes to a wide range of glomerular diseases. Factor H is the
main regulator of this innate immune cascade. Although some patients with kidney disease have underlying
defects in factor H, complete deficiency of the protein is quite rare. It is not clear why kidney is so frequently
the target of alternative pathway-mediated injury. One possible explanation is that endogenous proteins can
function as factor H antagonists, effectively creating microenvironments locally deficient in the regulator. The
factor H related proteins (FHRs), for example, antagonize binding of factor H to tissue surfaces, including
the glomerular basement membrane (GBM). We have also discovered that another class of proteins - the
annexins - act as factor H antagonists on kidney surfaces. Although the FHRs and annexins probably block
factor H from binding other tissues in the body, the high concentration of alternative pathway proteins within
the glomerular capillaries causes preferential activation at this location. Based on these findings, the primary
hypothesis of this grant is that is that the GBM is uniquely susceptible to alternative pathway activation
because the dysregulatory proteins (FHRs and annexins) effectively block factor H from binding this surface,
yet it is simultaneously exposed to high concentrations of activating proteins. Alternative pathway activation
within the glomerulus generates C3a and C5a, which ligate receptors on resident myeloid cells and create
an inflammatory milieux within the kidney. Complement fragments generated in the kidney also stimulate T
cells and B cells systemically. To test this hypothesis, the following specific aims will be pursued. Aim 1)
Characterize the effects of dysregulatory proteins in the kidney. We will use in vitro and in vivo models to
explore the molecular mechanisms that cause alternative pathway activation in the kidney. Aim 2. Examine
the downstream effects of AP activation in the kidney. In this aim we will explore the downstream effects of
glomerular complement activation on cells throughout the kidney. We will also examine whether
complement activation in the glomeruli affects the adaptive immune response systemically. This could
represent a mechanism by which inflammation in the kidney increases production of autoantibodies,
creating a positive feed-back loop. Aim 3. Test novel strategies for blocking complement activation in the
kidney. In this aim we will test the ability of novel engineered proteins to reverse alternative pathway
dysregulation in the kidney. The project is expected to provide an overarching explanation for why the
kidney - among all the organs - is so uniquely susceptible to alternative pathway-mediated injury. These
studies will also test strategies for specifically blocking kidney inflammation. By targeting the underlying
molecular triggers of complement activation in the kidney, drugs can be designed to inhibit these pathologic
processes witho...

## Key facts

- **NIH application ID:** 10583769
- **Project number:** 2R01DK076690-15
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua M Thurman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $468,016
- **Award type:** 2
- **Project period:** 2008-07-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10583769

## Citation

> US National Institutes of Health, RePORTER application 10583769, Complement-mediated injury of the kidney: New mechanisms and novel therapies (2R01DK076690-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10583769. Licensed CC0.

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