Editorial Focus: Model for chronic overexpression of NGF challenges old paradigms: focus on “Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function”
نویسندگان
چکیده
NERVE GROWTH FACTOR (NGF) has been suggested to play a role in bladder pain by mediating inflammation (12) and functional changes in sensory and sympathetic neurons innervating the urinary bladder (5). Clinically, diseases such as interstitial cystitis/painful bladder syndrome (IC/PBS) have been associated with elevated urinary levels of NGF (10), and the urothelium of individuals with IC/PBS presents high expression of NGF (7). In addition, NGF is thought to play a predominant role in several lower urinary tract dysfunctions, including urinary incontinence and overactive bladder symptoms, such as urgency, frequency, and nocturia. The majority of studies has focused on a central mechanism of NGF involvement in hyperalgesic states. However, as NGF is produced by peripherally located target cells, such as the bladder epithelium, a role for peripheral NGF in the physiopathology of the end organ has been proposed. Urotheliumsecreted NGF binds to receptor complexes present on the nerve endings, is internalized, and provides trophic signals that support neuronal survival and function (Fig. 1). Although a consensus has been formed that NGF plays a fundamental role in lower urinary tract function and response to injury-induced referred hyperalgesia, the absence of an animal model with chronic NGF overexpression has hampered our understanding regarding the mechanisms underlying NGF activity in the lower urinary tract. One of the difficulties involved in chronic overexpression of NGF is that systemic administration of this neurotrophin can cause allodynia that can last for several weeks and can complicate the interpretation of the results (4). Another confounding factor is that the proform of nerve growth factor (proNGF) is also secreted and is biologically active (6). ProNGF is synthesized from two alternatively spliced transcripts of 25and 32-kDa isoforms (1). Posttranslation modification of ProNGF includes N-glycosylation that leads to a 40-kDa secreted protein. The 40-kDa form of proNGF is secreted in response to nerve stimulation, along with the proteases needed to generate the 13-kDa mature NGF (mNGF), or to degrade it (1). In this issue of the American Journal of Physiology— Regulatory, Integrative and Comparative Physiology, Schnegelsberg and collaborators took advantage of a highly innovative model using the urothelium-specific uroplakin II (UPII) promoter (15) to drive the chronic expression of mouse NGF in a tissue-specific manner (13). The results show that urothelial NGF overexpression in transgenic mice resulted in neuronal proliferation, focal increases in bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity (13). This model of stable NGF overexpression will open a new field of research by challenging old paradigms and will permit a better evaluation on the role of NGF in target organ development. In addition, this outstanding mouse model will contribute to a better understanding of how NGF contributes to inflammatory pain, angiogenesis, and wound healing. A difficulty in overexpressing NGF is that mNGF is seldom detected in tissues by immunoprecipitation or by immunohistochemical methods (1). This seems to be the case of the present work that presented sound evidence of NGF overexpression at the mRNA level but was unable to detect ectopic NGF immunoAddress for reprint requests and other correspondence: R. Saban, 800 Research Parkway, Rm. 410. Oklahoma City, OK 73104 (e-mail: ricardo-saban @ouhsc.edu). Fig. 1. Nerve growth factor (NGF) overexpression in the bladder urothelium. Schnegelsberg et al. (13) developed an elegant mouse model overexpressing NGF specifically in bladder urothelial cells. NGF should activate neurotrophin receptors (p75 and TrkA) and increase the survival of neurons present in different layers of the urinary bladder. In consequence, the plasticity of target structures such as the urothelium itself, blood vessels, and bladder smooth muscle will be altered. Faded arrows indicate the possibility that increased release of NGF by urothelial cells could directly activate neurotrophin receptors suggested to be present in the urothelium (14), blood vessels (3), and detrusor smooth muscle (9). Am J Physiol Regul Integr Comp Physiol 298: R532–R533, 2010; doi:10.1152/ajpregu.00001.2010. Editorial Focus
منابع مشابه
Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function.
NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplak...
متن کامل“ Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation , pelvic sensitivity and changes in urinary bladder function ” by Schnegelsberg
Nerve growth factor (NGF) has been suggested to play a role in bladder pain by mediating inflammation (12) and functional changes in sensory and sympathetic neurons innervating the urinary bladder (5). Clinically, diseases such as interstitial cystitis/painful bladder syndrome (IC/PBS) have been associated with elevated urinary levels of NGF (10) and the urothelium of individuals with IC/PBS pr...
متن کاملNeurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium.
Urothelium-specific overexpression of nerve growth factor (NGF) in the urinary bladder of transgenic mice stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency, and results in increased referred somatic hypersensitivity. Additional NGF-mediated pleiotropic changes might contribute to the increased voiding frequency and pelvic hypersensitivity observed in the...
متن کاملCALL FOR PAPERS Sensory and Effector Functions of the Urothelium Neurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium
Girard BM, Malley SE, Vizzard MA. Neurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium. Am J Physiol Renal Physiol 300: F345–F355, 2011. First published November 3, 2010; doi:10.1152/ajprenal.00515.2010.— Urothelium-specific overexpression of nerve growth factor (NGF) in the urinary bladder of transgenic mice stimulates neuronal sprouting in the u...
متن کاملPreserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation.
Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restra...
متن کامل