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    THE ROLE OF MATRICELLULAR SIGNALING IN POLYCYSTIC KIDNEY DISEASE

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    Issue Date
    2017-08-31
    Author
    Raman, Archana
    Publisher
    University of Kansas
    Format
    147 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular & Integrative Physiology
    Rights
    Copyright held by the author.
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    Abstract
    Polycystic kidney disease (PKD) is characterized by excessive enlargement of the kidney, due to the hyperplastic growth of renal epithelial cells, giving rise to fluid-filled cysts. Autosomal dominant PKD (ADPKD), the most common renal disorder, affects 12.5 million people and accounts for 10% of the patients receiving renal replacement therapy. In PKD, the cyst-lining epithelia display several molecular patterns characteristic of tissue development and repair. The expanding cysts are associated with aberrant proliferation and extensive extracellular matrix (ECM) remodeling and deposition, causing interstitial fibrosis, which results in the progressive decline of renal function in PKD patients. Our lab discovered that periostin, a matricellular protein involved in tissue repair, is highly overexpressed in kidneys of human ADPKD, Autosomal Recessive PKD (ARPKD) and several animal models of PKD. Periostin accumulates in the ECM adjacent to cysts and binds to the cell surface integrins to stimulate the proliferation of cystic cells. Genetic knockout of periostin in pcy/pcy mice, a slowly progressive model of PKD, significantly reduced cystic growth and fibrosis, demonstrating that periostin significantly contributes to the progression of renal cystic disease. The molecular mechanisms behind periostin-induced ADPKD progression remain unclear. Here, we show that periostin stimulates integrin-linked kinase (ILK), a scaffold protein essential for ECM-cell communication, leading to activation of the Akt/mTOR pathway and proliferation of human ADPKD cells. In addition, periostin induced the activation of focal adhesion kinase (FAK) and Rho-dependent actin stress fiber formation and migration of ADPKD cells. Periostin also regulates the expression of genes involved in integrin signaling, ECM deposition and cytoskeletal reorganization in ADPKD cells, consistent with periostin activation of cellular pathways involved in tissue repair. To determine if overexpression of periostin in the cyst-lining cells accelerates PKD progression, we generated pcy/pcy mice with selective overexpression of periostin in the collecting duct (CD) cells, the predominant site of cyst formation. CD-specific periostin overexpression accelerated the progression of cystic disease by significantly increasing renal mTOR activity, cell proliferation, cyst growth and interstitial fibrosis. In parallel studies, we found that pharmacologic inhibition and shRNA knockdown of ILK prevented periostin-induced Akt/mTOR signaling and ADPKD cell proliferation. Furthermore, selective knockdown of ILK in the CD cells of Pkd1fl/fl;Pkhd1-Cre mice, a rapidly progressive model of ADPKD, and in pcy/pcy mice, decreased renal Akt/mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis, and significantly improved renal function and survival. Our results indicate that aberrant expression of periostin stimulates ILK-Akt-mTOR mediated cell proliferation, FAK-Rho mediated cytoskeletal rearrangement and migration, and ECM production. We propose that blockade of ECM-integrin signaling holds potential to slow cyst growth and fibrosis in PKD.
    URI
    http://hdl.handle.net/1808/26892
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    KU Libraries
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    785-864-8983

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    Lawrence, KS 66045
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    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
     

     

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