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The role of CD248+ stromal cells in the pathogenesis of renal fibrosis

Smith, Stuart William (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Chronic kidney disease affects 10-13% of the population. The dominant processes that promote kidney disease, irrespective of the trigger, occur in the stromal compartment where fibrosis is considered the hallmark of progressive renal disease. Recent studies have highlighted the importance of the vasculature and the role of the renal pericyte as a progenitor of activated matrix-depositing stromal myofibroblasts, cells that drive the development of renal fibrosis.

CD248 is a 175 KDa type I transmembrane glycoprotein expressed at low levels in non-inflamed kidney by resident renal stromal cells (pericytes and myofibroblasts). In this thesis I demonstrate that CD248 expression is increased in a cohort of patients with progressive renal fibrosis (n=93). Furthermore, increased CD248 expression in the kidney stroma is an independent risk factor for the progression of renal disease. I have then used an established murine model of renal fibrosis (unilateral ureteric obstruction) to characterise the origin, phenotype and function of CD248+ cells in vitro and in vivo. A transgenic mouse, with a targeted disruption to the CD248 gene has been used to assess the causal role that CD248 plays in the pathogenesis of renal fibrosis. Mice deficient in CD248 are protected against myofibroblast accumulation, tissue fibrosis and microvascular rarefaction following renal injury. In vitro data suggests that this phenotype may be due to a defect seen exclusively in stromal cell, but not epithelial cell, function as a consequence of the loss of CD248. Taken together these studies suggest that CD248 represents a novel stromal cell specific target for the treatment of chronic kidney disease.

Type of Work:Ph.D. thesis.
Supervisor(s):Buckley, Christopher D
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:RC Internal medicine
Institution:University of Birmingham
ID Code:3337
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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