Expression and function of transforming growth factor-β isoforms and cognate receptors in the rat urinary bladder following cyclophosphamide-induced cystitis.
Numerous proinflammatory 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-β (TGF-β) isoforms and receptor (TβR) variants in the normal and inflamed (CYP-induced cystitis) rat urinary bladder. Our findings indicate that TGF-β (1, 2, and 3) and TβR (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-β signaling contributes to urinary bladder dysfunction following intermediate (48 h) CYP-induced cystitis. TβR-1 inhibition with SB505124 (5 μM) 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-β in lower urinary tract neuroplasticity following urinary bladder inflammation, 2) a functional role of TGF-β signaling in the afferent limb of the micturition reflex, and 3) urinary bladder TβR-1 as a viable target to reduce voiding frequency with cystitis.
Univ. of Vermont College of Medicine, Dept. of Neurological Sciences, D415A Given Research Bldg., Burlington, VT 05405. Margaret.Vizzard@uvm.edu.
Eric J
EJ
Gonzalez
Beatrice M
BM
Girard
Margaret A
MA
Vizzard
D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage; D018856:Cystitis, Interstitial / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D009130:Muscle, Smooth / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D001743:Urinary Bladder / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism*
D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D003520:Cyclophosphamide
cyclophosphamide; detrusor smooth muscle; inflammation; transforming growth factor-β; urothelium