# Targeting Podocyte-Endothelial Cell Crosstalk as a FSGS Therapy

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $704,524

## Abstract

PROJECT SUMMARY/ABSTRACT
The scope of the problem is that 50% of patients with focal segmental glomerulosclerosis (FSGS), the leading
cause of primary proteinuric glomerular disease in adults, progress to chronic kidney disease. Thus,
developing new treatment strategies to improve FSGS patient outcomes is of utmost importance. Yet, there is
a large unmet need in our mechanistic understanding of disease progression. The traditional view in FSGS is
that podocytes are central to its pathology and that they are the first cell type to be injured. A more
contemporary view is an expansion of this paradigm and includes injury to neighboring glomerular cells. This
grant will focus on glomerular endothelial cells (GEnCs). The rationale is that (1) in FSGS, GEnCs decrease in
number, loose their glycocalyx and their fenestrae widen; (2) patients with GEnC damage have the highest
rates of disease progression; (3) GEnC injury scores for all glomerular diseases are highest in FSGS; (4)
GEnC genes/biomarkers are linked to the lowest remission rates and poor long-term outcomes of FSGS. Yet
the understanding of how podocytes cause secondary GEnC injury is very incomplete. To begin to close the
knowledge gap, we undertook an in silico approach to identify paracrine ligand-receptor signaling networks
between podocytes and GEnCs. Surprisingly, we discovered that experimental and human FSGS results in a
senescence associated secretory phenotype (SASP) and an activated inflammasome phenotype in non-aged
podocytes, both of which are characterized by the secretion of distinct classes of signaling mediators. Our
preliminary data shows that inhibiting the NLRP3 inflammasome in podocytes improves GEnC health. Our
specific aims will test two hypotheses: Specific Aim #1 tests the hypothesis that SASP and inflammasome
activation from injured podocytes are responsible for GEnC damage. Specific Aim #2 tests the hypothesis that
interfering with the paracrine injury signals from injured podocytes is a therapeutic target to prevent GEnC dys-
function in FSGS. The innovative experimental approaches we will use include: (i) In vivo loss-of-function
validation using mutant mice, in which we can reduce/inhibit the SASP or inflammasome phenotypes in
podocytes in the setting of experimental FSGS, and then measure the impact on GEnC health; (ii) in vivo gain-
of-function validation using transgenic mice, in which we can forcibly induce either a SASP or inflammasome
phenotype in podocytes to understand the impact on GEnCs; (iii) Quality-by-Design utilizing a systematic, high
complexity approach based on the Design-of-Experiment theory and Multivariate Data Analysis to address the
contribution of the podocyte secretome on GEnC health and function. As such, this proposal is highly
significant for its short-term impact on understanding the crosstalk between podocytes and GEnCs in FSGS,
and for its long-term impact in developing new therapeutic strategies to lower the risk and magnitude for
se...

## Key facts

- **NIH application ID:** 10862799
- **Project number:** 5R01DK135716-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Stuart James Shankland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $704,524
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862799

## Citation

> US National Institutes of Health, RePORTER application 10862799, Targeting Podocyte-Endothelial Cell Crosstalk as a FSGS Therapy (5R01DK135716-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10862799. Licensed CC0.

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