ALTERATION OF THE PKC-MEDIATED SIGNALING PATHWAY FOR SMOOTH MUSCLE CONTRACTION IN OBSTRUCTION-INDUCED HYPERTROPHY OF THE URINARY BLADDER

Normal urinary bladder function requires contraction and relaxation of the detrusor smooth muscle (DSM). The DSM undergoes compensatory hypertrophy in response to partial bladder outlet obstruction (PBOO) in both men and animal models. Following bladder hypertrophy, the bladder either retains its normal function (compensated) or becomes dysfunctional (decompensated) with increased voiding frequency and decreased void volume. We analyzed the contractile characteristics of DSM in a rabbit model of PBOO. The protein kinase C (PKC) agonist Phorbol 12, 13-dibutyrate (PDBu) elicited similar levels of contraction of DSM strips from normal or compensated bladders. However, PDBu-induced contraction decreased significantly in DSM strips from decompensated bladders. The expression and activity of PKC α were also lowest in decompensated bladders. The PKC specific inhibitor bisindolylmaleimide-1 (Bis) blocked PDBu-induced contraction and PKC activity in all three groups. Moreover, the phosphorylation of the phosphoprotein inhibitor CPI-17 was diminished in DSM from the decompensated bladder, which would result in less inhibitory potency of CPI-17 on myosin light chain phosphatase activity and contribute to less contractility. Immunostaining revealed the co-localization of PKC and phosphorylated CPI-17 in the DSM and confirmed the decreases of these signaling proteins in the decompensated bladder. Our results show a differential PKC-mediated DSM contraction with corresponding alterations of PKC expression, activity and the phosphorylation of CPI-17. Our finding suggests a significant correlation between bladder function and PKC pathway. An impaired PKC pathway appears to be correlated with bladder severe dysfunction observed in decompensated bladders.