Diabetic Cystopathy Correlates With a Long-Term Decrease in Nerve Growth Factor Levels in The Bladder and Lumbosacral Dorsal Root Ganglia

Abstract

PURPOSE It has been proposed that a deficiency in the axonal transport of nerve growth factor (NGF) may have an important role in inducing diabetic neuropathy, which contributes to diabetic cystopathy. Therefore, in streptozotocin (Sigma Chemical Co., St. Louis, Missouri) induced diabetic rats we investigated the relationship of bladder function with NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain afferent neurons innervating the bladder. MATERIALS AND METHODS At 6 and 12 weeks after the induction of diabetes with streptozotocin (65 mg./kg. intraperitoneally) the effects of diabetes on Adelta afferent fiber dependent, conscious voiding were evaluated by metabolic cage measurements and awake cystometry. The effects of diabetes on C-fiber mediated bladder nociceptive responses were also investigated by cystometry with intravesical instillation of 0.25% acetic acid in the rats under urethane anesthesia. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin injection. RESULTS In diabetic rats NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly decreased 12 weeks after streptozotocin injection (p <0.01). In cystometry and metabolic cage studies bladder capacity and post-void residual volume were significantly increased 12 weeks after streptozotocin injection (p <0.01). Bladder nociceptive responses revealed by a reduction in inter-contraction intervals after acetic acid infusion were significantly decreased in a time dependent manner 12 weeks after streptozotocin injection.CONCLUSIONS Rats with streptozotocin induced diabetes mellitus showed a significant time dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia that was associated with voiding dysfunction attributable to defects in Adelta and C-fiber bladder afferents. Therefore, reduced production of NGF in the bladder and/or impaired transport of NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may be an important mechanism inducing diabetic cystopathy.

Urologic Complications of Diabetes

“…It has been recently reported in STZinduced diabetic rats that decreased NGF levels in the bladder and lumbosacral dorsal root ganglia are associated with bladder dysfunction, suggesting the feasibility of NGF gene therapy for the treatment of diabetic cystopathy (36).…”

Efficacy of a Novel Device for Assessment of Autonomic Sensory Function in the Rat Bladder

“…Aδ-fiber and some C-fiber afferents are mechanosensitive and respond to bladder filling by providing information about bladder wall tension and volume 3,4 . Neuro-pathological conditions can selectively impair the functioning of specific subpopulation of nerve fibers while sparing the others 1,5 . Therefore, diagnosing dysfunction in specific subpopulations of bladder afferent fibers in the neurogenic bladder, may be helpful in guiding therapeutic intervention.…”

Proteomics Analysis Identifies Molecular Targets Related to Diabetes Mellitus-associated Bladder Dysfunction

“…For example, there are several publications suggesting that diabetes-associated bladder pathology is mainly a result of alterations in neuronal components, including deficiency of acetylcholinesterase (5-7), impaired ATPase activity (8,9), and diminished neurotrophic factor (10,11). Recently Sasaki et al (12) and Goins et al (13) showed the relation between bladder dysfunction and lower nerve growth factor levels and the feasibility of nerve growth factor gene therapy for treating diabetes mellitus (DM) 1 cystopathy.…”