Early molecular changes in bladder hypertrophy due to bladder outlet obstruction

Abstract

Objectives. To determine the temporal relationship between the increase in bladder mass and the expression of growth-associated gene products during bladder hypertrophy due to partial bladder outlet obstruction. Methods. Adult female rats, subjected to partial bladder outlet obstruction, were killed at defined points, and their bladder weight and total protein were determined and compared with sham-operated and nonoperated controls. Hyperplasia was determined by the expression of proliferating cell nuclear antigen, transcription factors, and cyclins in obstructed rat bladders. Bladder protein was fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and expression of the indicated proteins was determined by Western analysis and immunohistochemistry. Results. The mean bladder weight in sham-operated rats remained at 127 ± 17 mg, and the weight in the obstructed animals increased to 239 ± 56 mg at 12 hours, increasing to 486 ± 168 mg by 168 hours. The total bladder protein increased 1.8-fold after 12 hours and continued to increase for the duration of obstruction. The expression of proliferating cell nuclear antigen in the obstructed group did not begin until 24 hours of obstruction. The expression of the transcription factors, upstream binding factor, and c-Jun followed a similar pattern. Cyclin E and C expression increased most significantly after 48 hours. Conclusions. Bladder growth after 12 hours of partial outlet obstruction represents cellular hypertrophy based on the increases in bladder weight and total protein accumulation. Cellular hyperplasia occurs after 24 hours of obstruction as represented by increases in transcription factors and cell cycle-specific proteins.