# Neonatal Fc Receptor (FcRn) Trafficking of Immune Complexes to the Lysosome as a Driver of Glomerulonephritis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $406,894

## Abstract

Abstract/Project Summary
Immune mediated kidney diseases cause substantial morbidity and often lead to progressive renal failure.
Immune complexes (ICs) have been found in podocytes in a variety of immune mediated kidney diseases but it
is not known how podocytes handle immune complexes and whether trafficking of immune complexes in
podocytes exacerbates glomerulonephritis. The neonatal Fc receptor (FcRn) correctly sorts and traffics ICs in a
variety of cells including podocytes. FcRn is also required to traffic immune complexes to the lysosome in
dendritic cells for proteolytic processing and presentation on MHC II. In preliminary studies, we have found that
podocyte specific knockout of FcRn protects in two models of immune mediated nephritis but that this protection
is not conferred by an immune mediated mechanism. While there is no difference in any of the immune
parameters examined, we have found that there is significantly less apoptotic cell death and upregulation of
apoptotic pathways in FcRn knockout (KO) podocytes treated with immune complexes and significantly
decreased apoptosis in the glomeruli of podocyte specific FcRn KO mice after induction of nephrotoxic serum
nephritis (NTS). In addition, we have found significantly less lysosomal activation and less upregulation of
lysosomal enzymes in FcRn KO podocytes treated with immune complexes. Since FcRn is required to traffic
immune complexes to the lysosome, we hypothesize that in immune mediated nephritis, FcRn directed trafficking
of ICs to the lysosome results in lysosomal dysfunction, upregulation of the intrinsic apoptotic pathway and
podocyte death. To test this hypothesis we will directly examine lysosomal structure and function in WT and
FcRn KO podocytes after an immune challenge using both advanced imaging techniques and biochemical
methods. We will also examine whether FcRn mediated trafficking of immune complexes to the lysosome results
in increased lysosomal permeability and leakage of lysosomal cathepsins into the cytosol causing degradation
of mitochondrial membrane integrity, leakage of cytochrome c and upregulation of intrinsic apoptotic pathways.
We will test whether podocyte specific knockout of FcRn results in decreased lysosomal activation and improved
lysosomal function in podocytes in vivo after induction of immune mediated kidney disease (NTS) and whether
this in turn results in less apoptotic cell death, an increased number of viable podocytes and less severe disease
as assessed by functional and histologic parameters. Since upregulation of lysosomal cathepsins correlates with
more severe lupus nephritis in patients, we will also examine whether podocyte specific knockout of FcRn
ameliorates lupus nephritis in a spontaneous mouse model of this disease. Taken together, the proposed work
will provide novel insights into FcRn mediated trafficking of immune complexes in podocytes and may allow for
the creation of targeted therapies to slow or prevent progression of...

## Key facts

- **NIH application ID:** 10141982
- **Project number:** 2R01DK104264-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** JUDITH T., BLAINE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $406,894
- **Award type:** 2
- **Project period:** 2015-09-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141982

## Citation

> US National Institutes of Health, RePORTER application 10141982, Neonatal Fc Receptor (FcRn) Trafficking of Immune Complexes to the Lysosome as a Driver of Glomerulonephritis (2R01DK104264-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141982. Licensed CC0.

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