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dc.contributor.advisorWallace, Darren
dc.contributor.advisorBlanco, Gustavo
dc.contributor.authorRaman, Archana
dc.date.accessioned2018-10-22T15:46:01Z
dc.date.available2018-10-22T15:46:01Z
dc.date.issued2017-08-31
dc.date.submitted2017
dc.identifier.otherhttp://dissertations.umi.com/ku:15539
dc.identifier.urihttp://hdl.handle.net/1808/26892
dc.description.abstractPolycystic 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.
dc.format.extent147 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPhysiology
dc.subjectAutosomal dominant Polycystic kidney disease
dc.subjectECM
dc.subjectIntegrin-linked kinase
dc.subjectIntegrins
dc.subjectKidney
dc.subjectPeriostin
dc.titleTHE ROLE OF MATRICELLULAR SIGNALING IN POLYCYSTIC KIDNEY DISEASE
dc.typeDissertation
dc.contributor.cmtememberWallace, Darren
dc.contributor.cmtememberBlanco, Gustavo
dc.contributor.cmtememberApte, Udayan
dc.contributor.cmtememberCalvet, James
dc.contributor.cmtememberRao, Reena
dc.contributor.cmtememberYu, Alan
dc.thesis.degreeDisciplineMolecular & Integrative Physiology
dc.thesis.degreeLevelPh.D.
dc.identifier.orcidhttps://orcid.org/0000-0003-2819-4962
dc.rights.accessrightsopenAccess


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