Grant: Project Grant

Diabetes is the most common cause of kidney failure in Canada, and Hypertension (high blood pressure) accelerates the loss of kidney function in patients with diabetic kidney disease. Both, Diabetes and Hypertension damage the filtering capillaries of the kidney. Normally, these delicate capillaries have to withstand a higher than normal blood pressure to help drive filtration to produce urine, but they also have to keep blood proteins from escaping into the urine. Specialized cells called Podocytes cover these capillaries with long tentacle-like projections, providing strength and preventing proteins from escaping. A number of studies, including studies from our laboratory, have shown that Podocytes react to a higher than normal blood pressure and diabetes by rearranging their shape. In the short term these responses are protective, but in the long run they are counterproductive causing podocytes to detach, protein to leak into the urine, along with progressive scarring the filtering capillaries and eventually kidney failure. Our laboratory studies a protein called CLIC5A, which is a major Podocyte protein involved in the remodeling response. We have worked out some of the molecular mechanisms by which CLIC5A produces the normal shape of Podocyte projections. We have also shown that CLIC5A is essential for the Podocyte remodeling response to Hypertension and when CLIC5A is absent Hypertension-induced damage to the filtering capillaries of the kidney is dramatically increased. More recent, as yet unpublished work indicates that CLIC5A also participates in the Podocyte response to Diabetes. Using cultured Podocytes and Mouse Models, the current project aims to work out how CLIC5A and its protein partners orchestrate the Podocyte remodeling response to Diabetes in the presence and absence of Hypertension. Our long-term aim is to develop approaches that modify the Podocyte remodeling response and prevent Diabetes- and Hypertension-induced Kidney Failure.