Role of p75 in female rat urinary bladder with cyclophosphamide- induced cystitis

Klinger MB, Vizzard MA. Role of p75 in female rat urinary bladder with cyclophosphamide-induced cystitis. Am J Physiol Renal Physiol 295: F1778–F1789, 2008. First published October 8, 2008; doi:10.1152/ajprenal.90501.2008.—Previous studies demonstrated changes in urinary bladder neurotrophin content and upregulation of neurotrophin receptors, TrkA and the p75 neurotrophin receptor (p75), in micturition reflex pathways after cyclophosphamide (CYP)-induced cystitis. p75 can bind nerve growth factor (NGF) and modulate NGF-TrkA binding and signaling. We examined p75 expression and the role of p75 in the micturition reflex in control and CYP-treated rats. p75 Immunoreactivity was present throughout the urinary bladder. CYP-induced cystitis (4 h, 48 h, chronic) increased (P 0.05) p75 expression in whole urinary bladder as shown by Western blotting. The role of p75 in bladder function in control and CYP-treated rats was determined using conscious cystometry and immunoneutralization or PD90780, a compound known to specifically block NGF binding to p75. An anti-p75 monoclonal antibody or PD90780 was infused intravesically and cystometric parameters were evaluated. Both methods of p75 blockade significantly (P 0.05) decreased the intercontraction interval and void volume in control and CYP-treated rats. Intravesical infusion of PD90780 also significantly (P 0.001) increased intravesical pressure and increased the number of nonvoiding contractions during the filling phase. Control intravesical infusions of isotype-matched IgG and vehicle were without effect. Intravesical instillation of PD90780 significantly (P 0.01) reduced the volume threshold to elicit a micturition contraction in control rats (no inflammation) and CYP-treated in a closed urinary bladder system. These studies demonstrate 1) ubiquitous p75 expression in urinary bladder and increased expression with CYP-induced cystitis and 2) p75 blockade at the level of the urinary bladder produces bladder hyperreflexia in control and CYP-treated rats. The overall activity of the urinary bladder reflects the balance of NGF-p75 and NGF-TrkA signaling.