Grant: Travel Awards - Institute Community Support

The main function of the kidneys is to filter the blood of waste products and produce urine. Within the kidneys are millions of glomeruli (singular:glomerulus) which are the sites where urine formation begins. The glomerulus functions as a filtration barrier that prevents the loss of important blood proteins into the urine. Nephrotic Syndrome (NS) is a disorder of the kidney in which this filtration barrier is damaged and blood proteins are lost into the urine. It is common among children. The consequences of heavy protein loss can include edema (swelling), infections, blood clots and in severe cases, the need for dialysis or kidney transplantation to halt the protein loss. The severity and responsiveness to steroids is variable in NS. The kidney's filtration barrier contains a population of cells known as podocytes that are necessary for filtration function. Podocytes have a unique three-dimensional architecture with numerous small projections called foot processes that physically wrap around blood vessels, thereby blocking protein spillage into the urine. A family of proteins called Rho-GTPases regulate the three dimensional architecture of podocytes. The protein known as Rac1, is a key member of the Rho-GTPase family and it is necessary to maintain the three dimensional architecture of podocytes and for them to function properly. It is important that Rac1 activity is properly regulated in podocytes. We have genetically engineered experimental mice that express a hyper-active mutant form of Rac1 specifically within podocytes. When the hyper-active Rac1 is induced in these mice, they exhibit protein loss in the urine, kidney scarring and other problems associated with diseases of the glomerulus. We propose to study in detail how Rac1 affects the health of podocytes and how this protein can be targeted to treat NS, thereby improving the quality of the lives of people afflicted with the disease.