Naoko Iguchi1, Amy Hou1, Hari K Koul1, Duncan T Wilcox2. 1. Division of Urology, Department of Surgery, University of Colorado School of Medicine and Children's Hospital Colorado (AH, DTW), Aurora, Colorado. 2. Division of Urology, Department of Surgery, University of Colorado School of Medicine and Children's Hospital Colorado (AH, DTW), Aurora, Colorado. Electronic address: Duncan.Wilcox@childrenscolorado.org.
Abstract
PURPOSE: Posterior urethral valves are the most common cause of partial bladder outlet obstruction in the pediatric population. Posterior urethral valves is a devastating clinical problem that ultimately results in urinary incontinence, neurogenic bladder and renal impairment. Despite improvements in medical and surgical management at least a third of patients with this condition progress to end stage renal disease and half will have problems with urinary incontinence. To achieve better understanding of the mechanism associated with clinical events we generated partial bladder outlet obstruction in male mice. In this model we investigated pathological consequences and underlying molecular mechanisms secondary to partial bladder outlet obstruction. MATERIALS AND METHODS: Five to 8-week-old male C57BL/6 mice were divided into a surgical obstruction group and a sham operated group that served as controls. Bladders and kidneys were harvested from each group 1, 2, 3, 5 and 7 days postoperatively, respectively. We examined histological and biochemical alterations, and further investigated our hypothesis that partial bladder outlet obstruction induces hypoxia activated profibrotic signaling and changes in gene expression in the bladder. RESULTS: Mice with partial bladder outlet obstruction demonstrated significant increases in bladder mass and urinary retention compared to sham operated mice. Obstruction caused fibrosis in the bladder and induced up-regulation of profibrotic genes, hypoxia-inducible factors and epithelial-mesenchymal transition-inducing transcription factors, resulting in E-cadherin down-regulation. CONCLUSIONS: Obstruction induced significant histological and molecular alterations, including activation of the hypoxia-inducible factors pathway in the mouse bladder. Activation of epithelial-mesenchymal transition-inducing transcription factors by hypoxia-inducible factors might have an important role in the pathogenesis of partial bladder outlet obstruction.
PURPOSE: Posterior urethral valves are the most common cause of partial bladder outlet obstruction in the pediatric population. Posterior urethral valves is a devastating clinical problem that ultimately results in urinary incontinence, neurogenic bladder and renal impairment. Despite improvements in medical and surgical management at least a third of patients with this condition progress to end stage renal disease and half will have problems with urinary incontinence. To achieve better understanding of the mechanism associated with clinical events we generated partial bladder outlet obstruction in male mice. In this model we investigated pathological consequences and underlying molecular mechanisms secondary to partial bladder outlet obstruction. MATERIALS AND METHODS: Five to 8-week-old male C57BL/6 mice were divided into a surgical obstruction group and a sham operated group that served as controls. Bladders and kidneys were harvested from each group 1, 2, 3, 5 and 7 days postoperatively, respectively. We examined histological and biochemical alterations, and further investigated our hypothesis that partial bladder outlet obstruction induces hypoxia activated profibrotic signaling and changes in gene expression in the bladder. RESULTS:Mice with partial bladder outlet obstruction demonstrated significant increases in bladder mass and urinary retention compared to sham operated mice. Obstruction caused fibrosis in the bladder and induced up-regulation of profibrotic genes, hypoxia-inducible factors and epithelial-mesenchymal transition-inducing transcription factors, resulting in E-cadherin down-regulation. CONCLUSIONS: Obstruction induced significant histological and molecular alterations, including activation of the hypoxia-inducible factors pathway in the mouse bladder. Activation of epithelial-mesenchymal transition-inducing transcription factors by hypoxia-inducible factors might have an important role in the pathogenesis of partial bladder outlet obstruction.
Authors: Nao Iguchi; M İrfan Dönmez; Alonso Carrasco; Duncan T Wilcox; Ricardo H Pineda; Anna P Malykhina; Nicholas G Cost Journal: Am J Physiol Renal Physiol Date: 2019-05-08