Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium

Abstract

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, p75NTR) transcripts expression in tissues from NGF-OE and wildtype (WT) mice with CYP-induced cystitis of varying duration (4 h, 48 h, 8 d). 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 d) was not further increased but maintained with all durations of CYP treatment evaluated. In contrast, CYP-induced cystitis (4 h, 48 h, 8 d) in NGF-OE mice demonstrated significant (p ≤ 0.05) regulation in BDNF, VEGF, TrkA, TrkB and P75NTR mRNA in urothelium and detrusor smooth muscle. Similarly, CYP-induced cystitis (4 h, 48 h, 8 d) in NGF-OE mice resulted in significant (p ≤ 0.05), differential changes in transcript expression for NGF, BDNF and receptors (TrkA, TrkB, p75NTR) 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.

The Effect of Chronic Psychological Stress on Lower Urinary Tract Function: An Animal Model Perspective

“…Dorsal root ganglions may positively participate in these enhanced signal transductions ( Girard et al, 2020 ). Spinal sensitization has been identified in other non-stressed animal models ( Zvarova and Vizzard, 2006 ; Arms et al, 2013 ; Chen et al, 2016 ; Girard et al, 2016 ; Ozaki et al, 2018 ).…”

Urine: Waste product or biologically active tissue?

“…Growth factors, including epithelial growth factor (EGF) and fibroblast growth factor receptor (FGFR), also may regulate different urinary epithelia, given the high level of exposure to toxins and the mechanical demands on the bladder . Several growth factors such as NGF, BDNF, and VEGF can be released following inflammatory triggers and directly act on their associated receptors …”

“…39 Several growth factors such as NGF, BDNF, and VEGF can be released following inflammatory triggers and directly act on their associated receptors. 40…”

Imatinib Mesylate Reduces Neurotrophic Factors and pERK and pAKT Expression in Urinary Bladder of Female Mice With Cyclophosphamide-Induced Cystitis

“…These functional and inflammatory changes are recapitulated in a cyclophosphamide (CYP)-induced cystitis animal model. CYP treated rodents exhibit decreased time between voiding (i.e., intermicturition intervals, IMIs), decreased infused volume into the bladder to elicit a micturition event (i.e., infused volume, IV), void volume, and increased bladder pressure, afferent nerve excitability and somatic sensitivity (Yoshimura and de Groat, 1999;Boucher et al, 2000;Arms et al, 2013;Gonzalez et al, 2016;Guo et al, 2018) along with altered inflammatory mediator (e.g., growth factors, chemokines, cytokines, and related receptors) expression in the urinary bladder layers and associated dorsal root ganglia (DRG) and spinal cord levels (Malley and Vizzard, 2002;Klinger et al, 2007Arms et al, 2010Arms et al, , 2013Merrill et al, 2012;Gonzalez et al, 2013;Guo et al, 2018).…”