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NUCLEAR TRANSLOCATION OF WT1-INTERACTING PROTEIN IN RESPONSE TO PODOCYTE INJURY

Rico-Salas, Maria Isabel
http://rave.ohiolink.edu/etdc/view?acc_num=case1112886373

Abstract Details

2005, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
In kidney diseases the initial insult is to the glomerulus. Glomerular Injury causes structural abnormalities that conclude in the progressive loss of glomerular function, scarring and segmental sclerosis, which progress towards global sclerosis, degeneration of the tubule and interstitial fibrosis. Sclerotic glomeruli are not functional and effacement of the podocyte foot process is commonly observed. Recent studies have shown that foot process effacement is a consequence of a step down in the differentiated phenotype of the podocyte. Moreover, mutations in the Wilm’s Tumor suppressor gene (wt-1), which controls podocyte differentiation, have been identified in patients with nephritic syndromes. Also, animal models with deletions or lower genetic doses of the wt-1 gene developed proteinuria and glomerulosclerosis. Indicating that podocyte differentiation is critical for the function of the blood-to-urine barrier. In support of this, expression and localization of proteins that are elements of the slit diaphragm, a modified adherens junction, are altered in animal models of proteinuria. However, the molecular mechanisms underlying the initial steps of podocyte detachment and foot process effacement are obscure. We have viii previously identified a WT1 Interacting Protein (WTIP) that is a co-modulator of WT1 transcriptional activity. Here, we demonstrate that WTIP localizes to the adherens junction of podocytes and translocates to the nucleus upon injury with PAN. The junctional protein ZO-1, a member of the slit diapragm, also translocates to the nucleus of the podocyte because of this treatment. We observe downregulation of the WT1-induced Rbbp7 protein. To compliment our studies functionally, we developed an albumin diffusion assay and observed that diffusion of albumin in this system is dependent of podocyte differentiation. Treatment with PAN increased albumin diffusion to levels not distinguishable from undifferentiated podocytes, while this treatment did not affect albumin diffusion when other epithelial cell lines were used as control. We propose that WTIP is an environmental sensor at the slit diaphragm junction which, upon injury, translocates to the nucleus of the podocyte to repress WT1-dependent gene expression thus driving dedifferentiation. This would promote changes in the actin cytoskeleton that promote disassembly of the slit diaphragm, proteinuria, glomerular hypertrophy and ultimately glomerulosclerosis and kidney failure.
John Sedor (Advisor)
Kidney; Podocyte; Glomerulus; Proteinuria; Dedifferentiation; Plasticity; Gene Expression; Nuclear translocation; WT-1; WTIP; ZO-1; Adhesion; Differentiation

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Citations

  • Rico-Salas, M. I. (2005). NUCLEAR TRANSLOCATION OF WT1-INTERACTING PROTEIN IN RESPONSE TO PODOCYTE INJURY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1112886373

    APA Style (7th edition)

  • Rico-Salas, Maria. NUCLEAR TRANSLOCATION OF WT1-INTERACTING PROTEIN IN RESPONSE TO PODOCYTE INJURY. 2005. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1112886373.

    MLA Style (8th edition)

  • Rico-Salas, Maria. "NUCLEAR TRANSLOCATION OF WT1-INTERACTING PROTEIN IN RESPONSE TO PODOCYTE INJURY." Doctoral dissertation, Case Western Reserve University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1112886373

    Chicago Manual of Style (17th edition)

case1112886373
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© 2005, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.