# Pathophysiology of FSGS

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2024 · $327,360

## Abstract

PROJECT SUMMARY
Canonical transient receptor potential-6 (TRPC6) channels drive certain familial forms of focal and segmental
glomerulosclerosis (FSGS) and there is evidence that they contribute to much more common acquired forms
of FSGS and to renal fibrosis. TRPC6 dysregulation in podocytes occurs in animal models of FSGS, and in
podocytes exposed to serum or plasma from patients with recurrent FSGS, or in cells treated with the soluble
urokinase receptor (suPAR). While it is known that TRPC6 activation is required for Ca2+ influx driven by e.g.
angiotensin II, the Ca2+-permeability of TRPC6 is quite limited, and there are many conditions in which TRPC6
functions primarily as a monovalent cation channel. This fundamental property of TRPC6 suggests that while
it is necessary, it may not be sufficient to drive Ca2+ overload in podocytes or other cells. Specific Aim 1 of
this proposal tests the hypothesis that TRPC6 is part of a multichannel complex that includes KCa1.1
channels, and that coordinated KCa1.1 activation is necessary for TRPC6 to drive significant Ca2+ influx into
podocytes. KCa1.1 is a Ca2+-activated K+ channel that interacts with TRPC6 and other slit diaphragm proteins
including nephrin, Neph1, and podocin. Preliminary data show that KCa1.1 activation in podocytes is coupled
to TRPC6, and that KCa1.1 is dysregulated in an animal model of FSGS and in response to recurrent FSGS
plasma samples or suPAR. Specific Aim 1 will characterize changes in KCa1.1 gating and current density in
glomerular disease models previously shown to alter TRPC6. Quantitative Ca2+ imaging will address if KCa1.1
or its auxiliary β- and γ-subunits facilitate TRPC6-dependent Ca2+ influx into podocytes, which drives normal
cell signaling as well as pathological Ca2+ overload. There is now extensive evidence that suPAR contributes
to progression of multiple kidney diseases, including some cases of primary FSGS, but the mechanisms of
its signaling pathways are not well understood. Preliminary data show that the receptor for advanced glycation
endproducts (RAGE) functions as an essential co-receptor for suPAR on the pathway leading to Rac1,
oxidative stress, c-Src, and dysregulation of podocyte TRPC6. Specific Aim 2 will examine the role of RAGE
in driving albuminuria and glomerulosclerosis in a mouse model (suPAR2-Tg) that overexpresses a suPAR
variant in adipocytes and secretes it into the circulation. These mice exhibit albuminuria that later progresses
to glomerulosclerosis in a manner similar to human FSGS. In Specific Aim 2 we will cross suPAR2-Tg mice
with mice homozygous for an inducible knockout of RAGE. We will induce RAGE knockout both prior to and
after the onset of albuminuria. We will also determine if two different small molecule RAGE antagonists reduce
albuminuria and glomerulosclerosis in suPAR2-Tg mice. One of these antagonists, azeliragon, is orally
bioavailable in mice and humans, and is currently undergoing a Phase 2/3 clinical trial in a subs...

## Key facts

- **NIH application ID:** 10747320
- **Project number:** 5R01DK104708-08
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** STUART E DRYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $327,360
- **Award type:** 5
- **Project period:** 2015-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747320

## Citation

> US National Institutes of Health, RePORTER application 10747320, Pathophysiology of FSGS (5R01DK104708-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10747320. Licensed CC0.

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