Epigenetic mechanisms in a novel model of FSGS

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 complex significantly alters mitochondrial function and lipid metabolism defining new mechanisms in the programming of adult-onset disease. Our research team has complimentary expertise in

kidney development and disease, gene regulation, cell metabolism and bioinformatic analysis of mutli-omic data. Functional defects in lipid metabolism and mitochondrial function during post-natal kidney development will be examined to define biological processes that drive the development of adaptive (secondary) FSGS. We

will investigate how changes in genomic binding of NuRD and Zbtb7a/b in Mta2 mutants disrupts expression of genes that regulate cell metabolism in glomeruli and proximal tubules during post-natal maturation of the kidney. We will identify and functionally characterize genomic enhancers in mouse and human kidney relevant

to FSGS pathogenesis. These genome-wide data sets will be integrated with complementary multi-omics data in human kidneys (PCEN, KPMP, Nephroseq, Trident) and be of significant value to other investigators in the field. The long-term goal of our research is to identify early epigenetic events that trigger secondary FSGS

which are amenable to interventions that will prevent or substantially reduce the risk of this disease.