In many glomerular diseases, proteinuria and disease progression are associated with podocyte loss by death or detachment. Understanding the mechanisms by which the podocyte maintains attachment and recovers by remodeling its large and foot processes after injury is critical for the identification of potential therapeutic targetsof glomerular diseases. Podocalyxin is an apical membrane protein that is required for the formation of podocyte large and foot processes. A decrease in the sialylation and expression of podocalyxin are associated with glomerular diseases. Chloride intracellular channel 5 (CLIC5) is an apical membrane protein that associates with podocalyxin and ezrin, and is an important intermediate adapter between the cell membrane and the cytoskeletal network. We have recently discovered that CLIC5-deficient podocytes display foot process effacement and a decrease in podocalyxin protein expression. CLIC5 protein expression is decreased in Minimal Change Disease compared with normal human living donors. Our long term goal is to identify and understand the proteins and signaling pathways necessary for podocyte survival and remodeling in response to glomerular injury.
The aims of this proposal are twofold. First, we will determine the extent to which CLIC5 controls the proper trafficking and stability of podocalyxin in podocyte processes. Second, we will identify the role of CLIC5 in maintaining podocyte adhesion in response to glomerular injury in vivo. This project is significant because we will demonstrate a novel mechanism that is critical for podocyte recovery from injury. A combination of biochemical and cell biological approaches will be employed in cultured Clic5-deficient podocytes and Clic5-deficient mice. We expect to identify CLIC5 as a protein critical for podocytes to recover by maintaining their adherence to the glomerular matrix and to remodel their foot processes to reestablish the glomerular filtration barrier. The results of these experiments may aid in establishing a foundation for the rational design of effective clinical interventions for glomerular diseases.
The proposed project is relevant to public health because glomerular diseases are the leading cause of end stage and chronic kidney diseases. We will focus on identifying and understanding the proteins involved in controlling the survival and remodeling of podocytes, the main target cell of injury in many glomerular diseases.