# Epigenetic mechanisms in a novel model of FSGS

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2024 · —

## Abstract

Focal segmental glomerulosclerosis (FSGS) is a pathologic descriptive diagnosis of glomerular scarring
(fibrosis). Many types of kidney injury including inherited mutations, drug toxicity, loss of nephron mass and
autoimmune diseases are associated with this pattern of injury. In some cases, termed primary FSGS, the
underlying insult is not identified. It is likely that a complex interplay between genetic and environmental factors
is responsible for this disorder. However, progress in developing effective therapies for this common cause of
end-stage kidney disease has been hindered by a lack of understanding of the basic molecular mechanisms.
 There is compelling evidence that the intrauterine environment and post-natal growth can have significant
effects on kidney function and subsequent development of adult-onset disease. This process, known as
developmental programming, can have far-reaching implications for kidney, cardiovascular and metabolic
function. Significant risk factors of developmentally programmed chronic kidney disease (CKD) and HTN, such
as low birth weight and prematurity, are more common among African Americans, a population that is
disproportionately represented among veterans. A moderate reduction in nephron endowment, which is
typically clinically silent, is a risk factor for FSGS but is not sufficient to cause disease. Additional factors
(“second hits”) determine whether the kidney can adequately compensate for low nephron number or if
maladaptive structural and functional changes lead to disease. Post-natal growth and maturation of the kidney
play an important role in developmentally determined diseases because this period represents a window of
susceptibility to insults (“second hits”) causing permanent morphological changes and functional adaptation.
 Recent studies indicate that mitochondrial dysfunction during intrauterine and early post-natal growth may
be a common underlying mechanism for developmental programming of adult-onset diseases such as CKD
and HTN. We discovered that metastases associated protein 2 (Mta2), a core component of the Nucleosome
Remodeling and Deacetylase (NuRD) chromatin-remodeling complex is a critical regulator of genes required
for mitochondrial function and lipid metabolism in the kidney. Deletion of Mta2 in the developing kidney leads to
a moderate reduction in nephron endowment (“first hit”). We posit that the nephrons that do form in the Mta2
mutant harbor epigenetic changes that persist and affect gene expression required for mitochondrial function
and lipid metabolism during post-natal growth and maturation of the kidney (“second hit”). Other metabolic
stressors, such as high fat diet, can also serve as a “second hit” in a susceptible kidney. As a result, the kidney
is incapable of meeting the metabolic and functional demands of post-natal life, leading to FSGS.
 We are using cutting edge technologies, such as Hi-ChIP and epigenomic editing, to test a novel paradigm
that the Mta2-NuRD c...

## Key facts

- **NIH application ID:** 10924486
- **Project number:** 1I01BX005944-01A2
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** MICHAEL I RAUCHMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10924486

## Citation

> US National Institutes of Health, RePORTER application 10924486, Epigenetic mechanisms in a novel model of FSGS (1I01BX005944-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10924486. Licensed CC0.

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