Kidney disease is the ninth leading cause of death according to the Centers for Disease Control data. The prevalence of end stage renal disease is approximately 1500 per million population in the United States and approximately 2 to 3% of the U.S. population has abnormal kidney filtration function. A recent analysis of NHANES data shows that the prevalence of chronic kidney disease (CKD) in the United States in1999- 2004 is higher than it was in 1988-1994. The risk for progressive kidney disease is rising out-of-proportion to the increasing incidence of systemic diseases associated with kidney injury, such as diabetes, hypertension and obesity. These data suggest that undefined genetic, biochemical and environmental mechanisms collaborate to promote progressive kidney injury in individuals with common chronic diseases. Abnormal glomerular filtration function is a major CKD phenotype. In health, the podocyte elaborates arborized, F-actin sculpted foot processes that organize slit diaphragm proteins to maintain filtration barrier function, but in disease, the podocyte simplifies into a more typical cuboidal epithelial cell. Mechanisms of podocyte phenotypic plasticity are incompletely understood. Activity of the transcription factor, WT-1, is required for normal podocyte structure and is repressed by the WT1 Interacting Protein (WTIP). We have previously demonstrated that WTIP dissociates from podocyte cell contacts after injury and translocates to the nucleus. WTIP translocation is associated with podocyte F-actin rearrangement, and we hypothesized that WTIP senses changes in the actin cytoskeletal dynamics. We propose two specific aims to further dissect the function of WTIP in podocytes. In the first Specific Aim, we propose to explore the role of WTIP in the regulation of F-actin assembly. We will then elucidate the role of WTIP as a sensor of dynamic actin assembly state (Specific Aim2). To further understand the role of WTIP in vivo, we propose to study the association of WTIP with cytoskeleton under conditions of various actin assembly states (Specific Aim2). The proposed role of WTIP as a molecular choreographer of podocyte morphology and transcription represents a novel concept in the understanding of the progression of kidney disease. The function of podocyte in the ultrafiltration barrier requires a highly dynamic actin cytoskeleton. Our study hopes to identify WTIP as a critical regulator of renal permselectivity, which is regulates actin assembly state under normal and pathological conditions.
|Kim, Jane H; Mukherjee, Amitava; Madhavan, Sethu M et al. (2012) WT1-interacting protein (Wtip) regulates podocyte phenotype by cell-cell and cell-matrix contact reorganization. Am J Physiol Renal Physiol 302:F103-15|
|Sedor, John R; Madhavan, Sethu M; Kim, Jane H et al. (2011) Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP). Trans Am Clin Climatol Assoc 122:184-97|
|Kim, Jane H; Konieczkowski, Martha; Mukherjee, Amitava et al. (2010) Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport. J Biol Chem 285:9995-10004|