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Congenital urinary tract obstruction : linking form and function.

University of British Columbia

Renal dysplasia associated with congenital urinary tract obstruction remains the major cause of end-stage renal disease in young children. The outcomes of the most severely affected boys with posterior urethral valves have not changed since the introduction of fetal intervention over twenty years ago. Poor outcomes likely reflect our limited understanding of the pathophysiology of congenital obstructive nephropathy. The first part of this thesis summarizes the challenges of diagnosis and management of this condition that are based on the assessment of fetal tubular function rather than on tests reflecting the degree of dysplastic changes. The importance of the new biomarker development based on proteomic techniques is also presented. One of the processes leading to renal dysplasia, epithelial-mesenchymal transition (EMT), is presented for the first time in human fetal kidneys in the initial study of this thesis. Characteristic changes of EMT in the collecting duct epithelium consist of the decreased expression of epithelial proteins, increased expression of mesenchymal proteins, disruption of the basement membrane, and deposition of extracellular matrix into the surrounding interstitium. Molecular and cellular signaling events of the phenotypic epithelial transition are presented in the subsequent study in which a modulatory role of Y-box binding protein-1 (YB-1) on EMT is described. Inactivation of YB-1 leads to attenuation of EMT, a fact that might have therapeutic implications and deserves further exploration. Cellular signaling pathways of EMT are also described in this study. The final project of this thesis describes clinical utility of the identified candidate proteins as urinary biomarkers of congenital obstructive nephropathy in patients with posterior urethral valves (PUV). The differential expression of proteins involved in EMT, renal fibrosis, and sensing of urine flow in patients with PUV and controls is presented, as well as their correlation to the degree of renal impairment. The results presented in this thesis contribute to our understanding of the pathophysiology of congenital obstructive nephropathy, and identify key proteins involved in this process that could be measured in urine and used as biomarkers of this devastating disease.

Text

2010-08-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/27646

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/