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Permanent link (DOI): https://doi.org/10.7939/R3JT4M

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The Study of Kidney Microvascular Injury and Repair Open Access

Descriptions

Other title
Subject/Keyword
Angiogenesis
Vascular injury
Kidney
Endothelial cells
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Haddad, George
Supervisor and department
Murray, Allan
Examining committee member and department
Hollenberg Morley (Physiology & Pharmacology)
Rayner, David (Pathology)
Jahroudi, Nadia (Medicine)
Thebaud, Bernard (Pediatrics)
Department
Department of Medicine
Specialization
Experimental Medicine
Date accepted
2013-06-05T13:33:53Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Thrombotic microangiopathies are group of diseases that refer to clinical and pathological syndromes where endothelial injury results in the manifestations of capillary thrombosis, microangiopathic hemolytic anemia, schistocytosis, and can lead to renal failure. In this thesis we aimed to study glomerular endothelial cell (GEC) injury and repair. We developed an animal model of GEC-specific injury that is based on the binding specificity of MOA lectin to the carbohydrate epitope expressed in the mouse renal microvasculature. The lectin was conjugated to saporin to enhance the killing activity. The lectin-saporin (L-S) caused a uniform and reproducible GEC injury that captured many features frequently observed in TMA cases. To study renal repair we isolated and characterized human endothelial progenitor cells (hEPC) that were injected into mice treated with a sublethal dose of L-S. The human cells persisted in the kidney microvasculature of injured mice for 4 days but not in the uninjured control group. We also identified a novel function of PI3K catalytic subunit p110β in angiogenesis where in vitro analysis showed that p110β knockdown caused a defect in tip cell differentiation and sprouting formation, and decreased cellular migration and proliferation. in vivo analysis demonstrated that endothelial-restricted p110β ablation rendered the mice more susceptible to kidney injury and impaired renal microvasculature repair. In addition, we demonstrated an important role for platelet-derived growth factor B (PDGFB) in initiating kidney GEC repair mechanism as systemic inhibition of PDGFB by soluble PDGF receptor β led to high morbidity in the mice treated with a sublethal dose of L-S. In this thesis we developed an important animal model that can be used to further our understanding about the GEC injury and the potential application of EPC transplantation for renal restoration, and to gain more insights about the endogenous factors that govern the kidney microvascular repair mechanism.
Language
English
DOI
doi:10.7939/R3JT4M
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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