Calcineurin Mediates Bladder Smooth Muscle Hypertrophy After Bladder Outlet Obstruction

Abstract

Bladder outlet obstruction (BOO) leads to compensatory bladder hypertrophy. However, the hypertrophy mechanism remains elusive. We report that calcineurin (Cn) is involved in bladder hypertrophy. Partial BOO was surgically induced in 10-week-old female Wistar rats. The bladder was excised 2, 4 and 6 weeks following surgery in 9 rats each. Histological study was performed at each time point. Cn expression was examined by Western blot analysis. Myosin heavy chain expression was evaluated on gels stained with Coomassie blue. Primary cultured bladder smooth muscle cells were infected with recombinant adenoviruses encoding a constitutive active form of CnA (DeltaCnA), CnB and lacZ, and cell size was measured. In histological findings bladder smooth muscle hypertrophy was observed 2 and 4 weeks after surgery. However, the thickened muscles became thinner 6 weeks after BOO. CnA expression 2 weeks after BOO increased 3.2-fold compared with that of controls. Expression significantly decreased 4 and 6 weeks after surgery. In contrast, CnB expression was unchanged throughout hypertrophy development. Changes in myosin heavy chain expression correlated with changes in CnA. We observed significant hypertrophy in DeltaCnA and CnB over expressing smooth muscle cells. Moreover, FK506, which is a potent inhibitor of Cn, blocked hypertrophy in DeltaCnA and CnB over expressing smooth muscle cells. These data suggest that Cn has an important role in the induction of bladder smooth muscle hypertrophy.