Chronic kidney disease (CKD) often leads to irreversible deterioration of renal function and progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health problem and data obtained from the USRDS reveals that the number of new cases of ESKD in the United States is projected to be 650,000by 2010, with accompanying Medicare expenditures of $28 billion. As glomerular diseases secondary to podocyte dysfunction contribute up to 90% of all ESKD, a detailed molecular and genetic approach to identify mechanisms for podocyte development and repair may give us new insights for developing therapeutic agents and targets. Currently the therapeutic options available to treat glomerular diseases are limited to Angiotensin Receptor Blockers. Angiotensin Converting Enzyme Inhibitor, Steroids, and Alkylating Agents. As many patients treated with these agents still progress to ESKD, this suggests that other mechanisms responsible for injury are likely involved. When podocytes are damaged, the cell body retracts resulting in effacement and subsequently, proteinuria. For effacement to occur, cells must regulate adhesive contacts between the glomerular basement membrane and the extracellular matrix, which is comprised of focal adhesions and integrins. The goal of this research project is to define the role of focal adhesion protein, Focal Adhesion Kinase (FAK), a critical regulator of cell movement, in podocyte regulation following injury. Preliminary results demonstrate that FAK is highly activated following podocyte injury and a conditional knockout mice lacking podocyte FAK expression appear resistant to injury in murine modes of nephrotic and nephritic syndromes.
The aim of the current proposal is to assess the functional relevance of FAK activation by inducing podocyte injury in-vivo and by knocking down podocyte FAK expression with shRNA, and mutating critical FAK regulatory sites in-vitro (Specific Aim 1). As a novel specific FAK inhibitor (Novartis) is currently available, the functional response to FAK inhibition in vivo will be tested before and after podocyte injury in mice using this compound (Specific Aim 2). Finally, to address FAK's role in its regulation of downstream signaling molecules such as inducing matrix metalloproteinase 2 (MMP-2) activity, mice as well as cell culture models defined in the first two specific aims will be utilized to determine the mechanism inducing injury (Specific Aim 3).
Kidney injury that results in inflammation, loss of protein, and blood in the urine often leads to irreparable damage that ultimately requires a kidney transplantation and/or dialysis to treat the affected patient. In the United States, the number of new cases of chronic kidney disease is projected to be greater than 650,000 by year 2010. Currently there are a limited number of therapeutic options available. The goal of the proposal is to define the mechanisms that are involved during kidney injury and to utilize inhibitors that antagonize against the offending agent(s) responsible for disease progression.
| Lausecker, Franziska; Tian, Xuefei; Inoue, Kazunori et al. (2018) Vinculin is required to maintain glomerular barrier integrity. Kidney Int 93:643-655 |
| Zhou, Han; Tian, Xuefei; Tufro, Alda et al. (2017) Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury. Sci Rep 7:9833 |
| Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438 |
| Mathew, Sijo; Palamuttam, Riya J; Mernaugh, Glenda et al. (2017) Talin regulates integrin ?1-dependent and -independent cell functions in ureteric bud development. Development 144:4148-4158 |
| Inoue, Kazunori; Balkin, Daniel M; Liu, Lijuan et al. (2017) Kidney Tubular Ablation of Ocrl/Inpp5b Phenocopies Lowe Syndrome Tubulopathy. J Am Soc Nephrol 28:1399-1407 |
| Tian, Xuefei; Ishibe, Shuta (2016) Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease. Nephrol Dial Transplant 31:1577-83 |
| Hassan, Hossam; Tian, Xuefei; Inoue, Kazunori et al. (2016) Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes. J Am Soc Nephrol 27:1055-65 |
| Inoue, Kazunori; Ishibe, Shuta (2015) Podocyte endocytosis in the regulation of the glomerular filtration barrier. Am J Physiol Renal Physiol 309:F398-405 |
| Tian, Xuefei; Kim, Jin Ju; Monkley, Susan M et al. (2014) Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest 124:1098-113 |
| Soda, Keita; Ishibe, Shuta (2013) The function of endocytosis in podocytes. Curr Opin Nephrol Hypertens 22:432-8 |
Showing the most recent 10 out of 12 publications
