Expression and function of transforming growth factor-β isoforms and cognate receptors in the rat urinary bladder following cyclophosphamide-induced cystitis

Numerous pro-inflammatory cytokines have been implicated in the reorganization of lower urinary tract function following cyclophosphamide (CYP)-induced cystitis. The present study investigated the functional profile of three pleiotropic transforming growth factor-beta (TGF-beta) isoforms and receptor (T beta R) variants in the normal and inflamed (CYP-induced cystitis) rat urinary bladder. Our findings indicate that TGF-beta (1, 2, and 3) and T beta R (1, 2, and 3) transcript and protein expression were regulated to varying degrees in the urothelium or detrusor smooth muscle following intermediate (48 h; 150 mg/kg ip) or chronic (75 mg/kg ip; once every 3 days for 10 days), but not acute (4 h; 150 mg/kg ip), CYP-induced cystitis. Conscious, open-outlet cystometry was performed to determine whether aberrant TGF-beta signaling contributes to urinary bladder dysfunction following intermediate (48 h) CYP-induced cystitis. T beta R-1 inhibition with SB505124 (5 mu M) significantly (p <= 0.001) decreased voiding frequency and increased bladder capacity (2.5-fold), void volume (2.6-fold), and intercontraction intervals (2.5-fold) in CYP-treated (48 h) rats. Taken together, these results provide evidence for 1) the involvement of TGF-beta in lower urinary tract neuroplasticity following urinary bladder inflammation, 2) a functional role of TGF-beta signaling in the afferent limb of the micturition reflex, and 3) urinary bladder T beta R-1 as a viable target to reduce voiding frequency with cystitis.