# Novel mechanisms of glomerular injury in primary membranous nephropathy

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2022 · $372,401

## Abstract

Novel mechanisms of glomerular injury in primary membranous nephropathy
Primary membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Injury is
initiated by the deposition of circulating auto-antibodies against podocyte antigens in the subepithelial space of
the basement membrane, leading to complement activation and formation of the C5b-9 membrane attack
complex (MAC). MAC-mediated sublytic injury is thought to cause podocyte damage and glomerular disruption.
However, a randomized controlled trial showed no benefit of anti-C5 antibody in disease remission in patients
with MN, suggesting that other MAC-independent mechanisms apply. Studies on MN pathophysiology have
been limited by the lack of reliable in vitro systems. We generated a new glomerulus-on-a-chip platform that we
will use as a tool to assess alternative mechanisms of injury in MN. Preliminary data suggest that complement
activation leads to C3a/C3aR signaling in podocytes, which induces loss of glomerular permselectivity due
to SNAIL-mediated signaling. Moreover, challenging current assumption in MN, we have found that
MN-serum leads to C3a/C3aR signaling also in glomerular endothelial cells and induces overexpression of
MMP9, thus suggesting a role of this signaling in regulating glomerular basement membrane-cell interaction.
These effects are prevented by a C3aR antagonist, suggesting the direct involvement of C3a in podocyte and
GEC damage and in glomerular basement membrane (GBM) degradation. Therefore, based on our
preliminary data we hypothesize that C3a/C3aR signaling not only plays a critical role in podocyte damage
but exert its effects also on GEC, leading to disruption of glomerular filtration barrier and loss of
permselectivity. To test our hypothesis, we will investigate the effects of C3a signaling, its mechanism(s) of
action and its role in GBM degradation both in vitro and in vivo. If confirmed, our findings will not only provide
novel evidence that multiple injury mechanisms are in play in PMN but will also inform us about potential
therapeutic targets that could prove useful for the development of new treatments for MN and other
proteinuric diseases.

## Key facts

- **NIH application ID:** 10433930
- **Project number:** 5R01DK123234-03
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Stefano Da Sacco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,401
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433930

## Citation

> US National Institutes of Health, RePORTER application 10433930, Novel mechanisms of glomerular injury in primary membranous nephropathy (5R01DK123234-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433930. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*