Valerie Anne Schumacher, Ph.D.

Lay Summary of the Project:

Nephrotic syndrome is a serious complication of kidney disease that occurs when abnormally large amounts of protein leak from the circulation into the urine (proteinuria). Normally, when the kidney filters our blood, in structures known as glomeruli, there is a barrier in glomeruli that prevents proteins from leaving the circulation, and it is vital to our health that this barrier be kept intact. Recently, it has become evident that highly specialized cells in the kidney called podocytes constitute a major component of this barrier. Podocytes are cells within glomeruli that have an “octopus-like” shape, and they send out long extensions, known as foot processes. These foot processes wrap themselves capillaries in the glomeruli, and maintaining these foot processes is crucial to maintaining the protein barrier and preventing proteins from leaving the circulation. Damage to podocyte foot processes consequently results in proteinuria and may even lead to kidney failure when damage is irreversible. However, there exist situations of temporary damage in which podocytes are capable of recovering their foot processes and re-establish the protein barrier, which is suggestive of the existence of an intrinsic mechanism to repair and/or regenerate foot processes.

Usually, when a cell is damaged, it can make new proteins and repair itself. Proteins are manufactured in cells by taking the DNA code in the cell nucleus, copying the code into RNA, and translating the RNA code into proteins. When a cell responds to damage by making new proteins, it usually first needs to make new RNA and then translate the RNA into protein. Finally, the new protein needs to be brought to where it is needed to repair the cell. Cells like podocytes that have long extensions have special challenges not faced by more simple cells, as it may be difficult to transport the new protein quickly enough to adequately respond to damage. My work suggests that podocytes may use an alternate process to respond to damage, especially in their long extended foot processes. Instead of making new RNA each time new proteins are needed, podocytes may maintain RNA in special structures known as RNA granules, and locate these RNA granules in foot processes. In this way, when a foot process is damaged, new proteins can be translated from RNA close to the point of damage, to repair the protein barrier. This mechanism may represent a novel route for pharmalogical interventions to improve regenerative capability of podocytes and thus to prevent or treat glomerular disease.