Transcription Factors as Therapeutic Targets in Focal Segmental Glomerular Sclerosis
Abstract
There are few more terrifying diagnoses than Focal Segmental Glomerulosclerosis (FSGS). The life expectancy of children or adults with this diagnosis is quite significantly reduced. Indeed, there are many forms of cancer with a better prognosis and that are far more treatable. Just as devastating is the extraordinary impact this disease has on the quality of life of the affected individual and their families. An individual with FSGS will likely spend several days each week undergoing dialysis. Having a family member under this type of treatment for FSGS would nearly or absolutely preclude having an active career in the United States military. Unfortunately, there have only been a few novel therapeutic modalities developed over the past several decades that improve the prognosis of individuals with FSGS. Why is FSGS such a devastating disease? Simply put, our kidneys maintain our normal physiology by regulating the amount of water and salt in our bodies, as well as removing otherwise toxic nitrogenous waste products, and FSGS renders the kidneys unable to do so. The structural unit that carries out filtration of our blood is called a nephron. Each human kidney has anywhere from several hundred thousand to nearly a million nephrons. At one end of each nephron is a microscopic spherical structure called the glomerulus, where the blood is actually filtered. Within each glomerulus, blood passes through several capillaries, (i.e., microscopic blood vessels). Wrapped around these capillaries are an unusual cell type called the podocyte. Podocytes are shaped like an octopus, with a central body, and multiple extensions, similar to the tentacles of the octopus. Therefore, one can imagine a glomerulus being a microscopic sphere, in which there are several loops of capillaries, and a bunch of podocytes, each extending its tentacle-like extensions around the capillaries, to form a scaffolding that supports those capillary loops. When blood is filtered, much of the water, salts, and sugars in our blood pass from the capillaries into the space inside the sphere where the podocytes are forming the scaffolding. That filtered water, salts, and sugars, then moves from the glomerulus into a long series of tubules comprising the remainder of the nephron, where reabsorption takes place, to return most of the water, salts, and sugars in the bloodstream. It is the amount of water, salt, and nitrogenous waste that is not reabsorbed, that is excreted as urine. Based on this explanation, it might seem that these tubules carrying out the reabsorption must be more important than the glomerulus, whose only job is to filter blood. Nothing could be further from the truth! Our blood is composed not only of water, salts, and sugars, but also has red and white blood cells. Our blood also contains many highly important proteins, such as antibodies that fight infection, and many hormones such as insulin. By far, the most abundant protein in our blood is one called albumin. Albumin in our blood is sufficiently concentrated that it serves to retain the water in our blood through a phenomenon known as oncotic pressure, a situation where large molecules such as proteins retain water molecules in the blood, rather than letting water diffuse out of blood vessels into surrounding tissues. Thus, filtration in our glomeruli must occur in such a way as to let the water, salts, and sugar pass out of our capillaries, but keep the cells and proteins such as albumin inside the capillaries. This selectively requires the presence of an exquisite filter that does not allow proteins to escape the capillaries. Podocytes are the essential cell that maintains this filter, largely through the extensions wrapped around the outer surfaces of the capillary loops. Each extension gives rise to many much smaller extensions, called foot processes, that are also attached to outer surface of the capillaries. If an extension from one podocyte is adjacent to an extension from a nearby p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210349
Entities
People
- Jordan Kreidberg
Organizations
- Beth Israel Deaconess Medical Center
- United States Army