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...