# Mechanisms of complement-mediated podocyte injury in FSGS

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $254,250

## Abstract

Summary
Focal
failure
recent
of
significant
hypothesis-driven
segmental glomerulosclerosis (FSGS) is a major cause of proteinuria and renal
that leads to end stage renal disease (ESRD) in over 50% of the cases. Despite
important advances in the understanding of FSGS etiopathogenesis, mechanisms
disease initiation and progression are still largely unknown. Limited efficacy and
toxicities associated with existing therapies urge for the identification of new,
approaches.
We reported the novel finding that, in Adriamycin and CD2AP-/- murine models of FSGS,
complement regulator decay accelerating factor (DAF) is downregulated on podocyte
membranes, which unleashes restraints to complement activation and leads to the
formation of C3a. Signaling of C3a/C3aR on podocytes results into cytoskeleton
rearrangement. Additional preliminary data indicate that, in humans with FSGS, DAF is
downregulated and urinary levels of C3a correlate with proteinuria and C3d deposition in
the glomeruli. This supports the hypothesis that, in murine and human FSGS, filtered
and/or kidney-produced complement components undergo activation through the
alternative pathway initiated by DAF downregulation and promote podocyte injury and
glomerulosclerosis through C3a/C3aR activation. We will test this hypothesis by
determining the source of urinary complement (systemic versus renal), the pathway of
complement activation (alternative, classical, or MBL), and the in vivo effect of
C3a/C3aR on podocytes (aim 1). We will also decipher the implicated molecular
mechanisms (aim 2).
The results of the research project will provide new insight on the role of complement in
FSGS pathogenesis regardless of outcome. The data have the potential to explain
previously published observations associating complement deposition in the glomeruli of
patients with FSGS with renal outcomes. Finally, the results could significantly change
clinical practice through providing supporting evidence for the use of complement or
complement receptor inhibitors to prevent or retard progression of FSGS and other
proteinuric glomerular diseases.

## Key facts

- **NIH application ID:** 10115529
- **Project number:** 5R01DK119431-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Paolo Cravedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115529

## Citation

> US National Institutes of Health, RePORTER application 10115529, Mechanisms of complement-mediated podocyte injury in FSGS (5R01DK119431-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115529. Licensed CC0.

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