KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    ROLE OF THE Na,K-ATPase IN POLYCYSTIC KIDNEY DISEASE

    Thumbnail
    View/Open
    umi-ku-2655_1.pdf (4.160Mb)
    Issue Date
    2008-07-31
    Author
    Nguyen, Anh-Nguyet Thi
    Publisher
    University of Kansas
    Format
    227 pages
    Type
    Dissertation
    Degree Level
    PH.D.
    Discipline
    Molecular & Integrative Physiology
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
    Metadata
    Show full item record
    Abstract
    Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disease, and is characterized by multiple fluid-filled cysts that impair the organ, ultimately leading to renal failure. Formation and enlargement of the cysts require abnormal proliferation and cell death, as well as changes in the transport properties of the renal tubule epithelial cells. Because of its primary role in the vectorial movement of salt and water in the kidney, the Na,K-ATPase has been the focus of investigation to understand the pathophysiology of ADPKD. However, the precise role of the transporter has not been identified. In this dissertation, we describe studies designed to characterize the Na,K-ATPase in ADPKD, and examine the mechanisms underlying its role in the disease. The transport properties of the Na,K-ATPase is regulated by the hormone ouabain, which inhibits its movement of the cations. In addition, ouabain binding to the Na,K-ATPase has been been found to activate a cascade of phosphorylating events, leading to cell growth. Interestingly, we have found a population of the Na,K-ATPase in human cystic epithelial cells to have a higher affinity for ouabain, at concentrations consistent with circulating levels of the hormone. Thus, nanomolar concentrations of ouabain that do not normally affect the activity of the Na,K-ATPase in the kidney partially inhibit the enzyme of cystic tissue and cells. The Na,K-ATPase has been found to interact with polycystin-1, and we have found this to association to increase the sensitivity of the enzyme to ouabain. Our hypothesis is that due to their increased sensitivity to the hormone in ADPKD, the cystic renal epithelium is more susceptible to the effects of endogenous ouabain. We found ouabain to stimulate both proliferation and apoptotic death of the ADPKD cells, causing a disbalance that favors increased cell growth. While the mitogenic effect of ouabain is mediated by activation of the epidermal growth factor receptor (EGFR), Src kinase and extracellular signal-regulated kinase (ERK) pathway, its apoptotic effect was found to be through activation of the intrinsic pathway of apoptotic cell death. We also found ouabain to exacerbate the development and growth of cysts, both in cultured human ADPKD cells and metanephric organ cultures from Pkd1m1Bei mice, a well characterized model of ADPKD. Collectively, these results demonstrate ouabain, acting through the Na,K-ATPase, is a novel agent that can adversely affect the progression of ADPKD.
    URI
    http://hdl.handle.net/1808/4233
    Collections
    • Dissertations [4475]
    • Molecular Biosciences Dissertations and Theses [270]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps