Remodeling of the collecting duct with urinary tract obstruction

• Main Author: Hiatt, Michael Joseph
• Language: English
• Published: University of British Columbia 2011
• Online Access: http://hdl.handle.net/2429/39806

Urinary tract obstruction is a major cause of morbidity and mortality worldwide. Obstruction occurs in both the fetus and adult, can lead to impaired renal development, substantial renal injury, dysplasia, or progressive fibrosis of the kidney. Though different in outcome, fetal and adult obstruction both impair normal kidney function and promote the onset of chronic kidney disease. While a substantial amount of research has identified key features in the pathogenesis of obstruction, our understanding of the early events in the progression of obstructive injury is incomplete. In this thesis, I have used several experimental models to investigate the role of medullary and collecting duct injury following urinary tract obstruction. Research using these models has provided many key findings. First, I have established the previously unreported ontogeny of the collecting duct in the human fetal kidney. Second, I have defined the impact of urinary tract obstruction on the collecting duct and linked it to collecting duct injury. Third, I have characterized the response of the collecting duct and associated renal interstitium to obstruction, and identified cellular dedifferentiation and phenotypic transition as common outcomes of collecting duct injury. Last, I have characterized the expression, localization and protein-complex formation of TRPV4, and highlighted a mechanism for TRPV4 in the transduction of physical injury into a collecting duct epithelial response. Through investigation of clinical cases of fetal urinary tract obstruction and experimentation using 2 models of fetal and adult obstruction, I have demonstrated that collecting duct epithelial injury and remodeling is a common and conserved feature of obstructive injury and I have described a role for TRPV4 in the mechanosensation and transduction of the physical stimuli caused by obstructive injury. I believe TRPV4-mediated signal transduction, in part, provides a unifying mechanism for the induction of a repair and fibrosis during both fetal and postnatal urinary tract obstruction.