Bladder muscle responds to the obstruction of BPH with hypertrophy and micturitional dysfunction. In general, muscle regulates gene expression in response to stretch. Alteration in muscle gene expression also causes changes in innervation patterns and micturition reflexes. These secondary neural changes may contribute to disease progression. Neural changes accompanying muscle hypertrophy and aging are mediated via neurotropic factors such as nerve growth factor (NGF). This proposal hypothesizes that stretch-induced responses and bladder pathophysiology involve at least one of the major intracellular signaling elements, protein kinase C (PKC). The hypothesized PKC involvement will be tested in vivo using a rat model of bladder outlet obstruction as well as cultured bladder muscle cells subjected to computer controlled mechanical deformation. The PKC isozyme(s) responding to stretch will be identified and whether the stretch response is specific to muscle will be determined. Responses of bladder from the spontaneously hypertensive rat (SHR) to obstruction, and isolated and cultured SHR cells also will be studied to examine whether these animals have a defective PKC signaling system that affects muscle mechanical responses, as preliminary data suggest. These results will elucidate signal pathways that link mechanical responses to muscle protein expression in bladder. This knowledge will advance understanding of bladder responses to mechanical force at the molecular level and may introduce novel therapeutic targets useful in treating the aging or hypertrophied detrusor.
