Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium.
We have determined if cyclophosphamide (CYP)-induced cystitis produces additional changes in growth factor/receptors expression in the urinary bladder (urothelium, detrusor) and lumbosacral (L6-S1) dorsal root ganglia (DRG) in a transgenic mouse model with chronic urothelial overexpression of NGF (NGF-OE). Functionally, NGF-OE mice treated with CYP exhibit significant increases in voiding frequency above that observed in control NGF-OE mice (no CYP). Quantitative PCR was used to determine NGF, BDNF, VEGF, and receptors (TrkA, TrkB, p75(NTR)) transcripts expression in tissues from NGF-OE and wild-type (WT) mice with CYP-induced cystitis of varying duration (4 h, 48 h, 8 days). In urothelium of control NGF-OE mice, NGF mRNA was significantly (p ≤ 0.001) increased. Urothelial expression of NGF mRNA in NGF-OE mice treated with CYP (4 h, 48 h, 8 days) was not further increased but maintained with all durations of CYP treatment evaluated. In contrast, CYP-induced cystitis (4 h, 48 h, 8 days) in NGF-OE mice demonstrated significant (p ≤ 0.05) regulation in BDNF, VEGF, TrkA, TrkB, and P75(NTR) mRNA in urothelium and detrusor smooth muscle. Similarly, CYP-induced cystitis (4 h, 48 h, 8 days) in NGF-OE mice resulted in significant (p ≤ 0.05), differential changes in transcript expression for NGF, BDNF, and receptors (TrkA, TrkB, p75(NTR)) in S1 DRG that was dependent on the duration-of CYP-induced cystitis. In general, NGF, BDNF, TrkA, and TrkB protein content in the urinary bladder increased in WT and NGF-OE mice with CYP-induced cystitis (4 h). Changes in NGF, TrkA and TrkB expression in the urinary bladder were significantly (p ≤ 0.05) greater in NGF-OE mice with CYP-induced cystitis (4 h) compared to WT mice with cystitis (4 h). However, the magnitude of change between WT and NGF-OE mice was only significantly (p ≤ 0.05) different for TrkB expression in urinary bladder of NGF-OE mice treated with CYP. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity with potential contributions to reflex function of micturition pathways.
Department of Neurological Sciences, University of Vermont College of Medicine, D405A Given Research Building, Burlington, VT, 05405, USA.
Beatrice M
BM
Girard
Department of Neurological Sciences, University of Vermont College of Medicine, D405A Given Research Building, Burlington, VT, 05405, USA.
Susan
S
Malley
Department of Neurological Sciences, University of Vermont College of Medicine, D405A Given Research Building, Burlington, VT, 05405, USA.
Victor
V
May
Department of Neurological Sciences, University of Vermont College of Medicine, D405A Given Research Building, Burlington, VT, 05405, USA. margaret.vizzard@uvm.edu.
Margaret A
MA
Vizzard
D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity; D003556:Cystitis / Q000209:etiology / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D001743:Urinary Bladder / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism*
D009414:Nerve Growth Factors; D003520:Cyclophosphamide; D020917:Receptor, trkA; D020813:Receptor, trkB
Cyclophosphamide; Cystitis; DRG; NGF; Transgenic mouse model; Urinary bladder; Urothelium