Endogenous Nerve Growth Factor Regulates Collagen Expression and Bladder Hypertrophy through Akt and MAPK Pathways during Cystitis

Abstract

Type I collagen forms the main constituent of the extracellular matrix in visceral organs. We reported here that cyclophosphamide (CYP)-induced cystitis significantly increased the production of type I collagen in the inflamed bladder leading to increases in the bladder weight and the thickness of the bladder wall. The endogenous nerve growth factor (NGF) in the urinary bladder regulated type I collagen expression because the neutralizing NGF antibody attenuated cystitisinduced type I collagen up-regulation in the inflamed bladder. Neutralizing NGF antibody also subsequently reversed cystitis-induced increases in bladder weight. Further studies on the intermediate signaling pathways mediating NGF-induced type I collagen expression in the inflamed bladder during cystitis revealed that Akt, JNK, and ERK1/2 activities were increased in the inflamed bladder, whereas p38 MAPK remained unchanged. Suppression of endogenous NGF level with neutralizing NGF antibody significantly blocked the increased activity of Akt, JNK, and ERK1/2 in the inflamed bladder during cystitis. These results indicate that endogenous NGF plays an important role in the activation of Akt and MAPK in the urinary bladder and in bladder hypertrophy during cystitis.

Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

“…Studies have previously demonstrated changes in AKT activation levels in primary sensory neurons, dorsal horn neurons, and the urinary bladder (16,53,59,60,71) following tissue inflammation. The present studies extend previous findings (16) by demonstrating a functional significance for AKT signaling in bladder reflex pathways.…”

“…These changes may be mediated, in part, by inflammatory changes in the urinary bladder. Potential mediators of bladder inflammation are numerous and include cytokines (23,40,43), neuropeptides (11,69), neuroactive compounds (9), chemokines (3,55,67,73) and growth factors (70,72,75) and signaling molecules such as pERK1/2 (16,17), pJNK (16, Vizzard et al, unpublished observations), and pAKT (4,16).…”

“…NGF interactions with the high-affinity receptor TrkA are known to activate the PI3-K/AKT, ERK1/2, and JNK signaling pathways. Chung et al (16) demonstrate that AKT and ERK1/2 phosphorylation in the urinary bladder with CYP-induced bladder inflammation is dependent on the presence of NGF, suggesting that NGF constitutes a major upstream activator of AKT phosphorylation in bladder inflammation; however, the involvement of NGF/TrkA and/or NGF/ p75 NTR interactions was not identified. Numerous rodent studies demonstrate the physiological relevance of NGF signaling in the urinary bladder (15,20,34,41,57,72,75).…”

“…Previous (17) and present studies now demonstrate that blockade of potential downstream NGF signaling targets, ERK1/2, or AKT activation, reduces urinary bladder hyperreflexia following CYPinduced cystitis. Whether cross talk exists between these two pathways in the context of urinary bladder inflammation (16) or whether further improvement in bladder function can be achieved by blocking both AKT and ERK1/2 activation remains to be determined.…”

“…CYP-induced cystitis increased ERK phosphorylation in the urinary bladder (16,17), and Corrow and Vizzard (17) demonstrated a functional role for pERK in micturition reflexes using an upstream inhibitor of ERK phosphorylation to significantly decrease CYP-induced bladder hyperreflexia in rats. Expression (16) as well as functional roles for JNK activation (Vizzard et al, unpublished observations) in the urinary bladder following cystitis have also been demonstrated. The current study addresses the contribution of AKT phosphorylation to micturition reflex function in a CYP model of urinary bladder inflammation.…”