TY - JOUR
T1 - A MAPP network study
T2 - Overexpression of tumor necrosis factor-α in mouse urothelium mimics interstitial cystitis
AU - Yang, Wenbin
AU - Searl, Timothy J.
AU - Yaggie, Ryan
AU - Schaeffer, Anthony J.
AU - Klumpp, David J.
N1 - Funding Information:
Studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases Awards R01-DK-066112 (D. J. Klumpp), U01-DK-82342 (MAPP Research Network; D. J. Klumpp and A. J. Schaeffer), and 1R01-DK-095775 (T. J. Searl) and generous salary support of T. J. Searl by Dr. Alfred George Jr., Chairperson of Pharmacology.
Funding Information:
We thank Dr. Tung-Tien Sun of New York University Medical School for kindly providing the UPII-lacZ plasmid and Dr. Brett Giroir of the University of Texas Southwestern Medical Center for kindly providing the MHC-TNF plasmid. We also thank Dr. Gerald Herrera of Catamount Research and Development for expert training in awake cystometry. Studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases Awards R01-DK-066112 (D. J. Klumpp), U01-DK-82342 (MAPP Research Network; D. J. Klumpp and A. J. Schaeffer), and 1R01-DK- 095775 (T. J. Searl) and generous salary support of T. J. Searl by Dr. Alfred George Jr., Chairperson of Pharmacology.
Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - Interstitial cystitis/bladder pain syndrome is a chronic bladder condition associated with pain and voiding dysfunction that is often regarded as a neurogenic cystitis. Patient symptoms are correlated with the presence of urothelial lesions. We previously characterized a murine neurogenic cystitis model that recapitulates mast cell accumulation and urothelial lesions, and these events were dependent on TNF. To further explore the role of TNF in bladder inflammation and function, we generated a transgenic mouse model with chronic TNF overexpression in urothelium under the control of the uroplakin II (UPII) promoter. Transgenic mouse lines were maintained by backcross onto wild-type C57BL/6J mice and evaluated for pelvic tactile allodynia as a measure of visceral pain, urinary function, and urothelial lesions. TNF mRNA and protein were expressed at greater levels in bladders of UPII-TNF mice than in those of wild-type mice. UPII-TNF mice showed significantly increased urinary frequency and decreased void volume. UPII-TNF mice had increased urothelial apoptosis and loss of urothelial integrity consistent with urothelial lesions. Overexpression of TNF was also associated with pelvic tactile allodynia. Consistent with these findings, UPII-TNF mice exhibited increased bladder afferent activity in response to stretch ex vivo. In summary, UPII-TNF mice display significant pelvic pain, voiding dysfunction, urothelial lesions, and sensory input. Thus UPII-TNF mice are a model for characterizing mechanisms of interstitial cystitis symptoms and evaluating therapies.
AB - Interstitial cystitis/bladder pain syndrome is a chronic bladder condition associated with pain and voiding dysfunction that is often regarded as a neurogenic cystitis. Patient symptoms are correlated with the presence of urothelial lesions. We previously characterized a murine neurogenic cystitis model that recapitulates mast cell accumulation and urothelial lesions, and these events were dependent on TNF. To further explore the role of TNF in bladder inflammation and function, we generated a transgenic mouse model with chronic TNF overexpression in urothelium under the control of the uroplakin II (UPII) promoter. Transgenic mouse lines were maintained by backcross onto wild-type C57BL/6J mice and evaluated for pelvic tactile allodynia as a measure of visceral pain, urinary function, and urothelial lesions. TNF mRNA and protein were expressed at greater levels in bladders of UPII-TNF mice than in those of wild-type mice. UPII-TNF mice showed significantly increased urinary frequency and decreased void volume. UPII-TNF mice had increased urothelial apoptosis and loss of urothelial integrity consistent with urothelial lesions. Overexpression of TNF was also associated with pelvic tactile allodynia. Consistent with these findings, UPII-TNF mice exhibited increased bladder afferent activity in response to stretch ex vivo. In summary, UPII-TNF mice display significant pelvic pain, voiding dysfunction, urothelial lesions, and sensory input. Thus UPII-TNF mice are a model for characterizing mechanisms of interstitial cystitis symptoms and evaluating therapies.
KW - Interstitial cystitis
KW - Pelvic pain
KW - TNF
KW - Transgenic mouse model
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UR - http://www.scopus.com/inward/citedby.url?scp=85050810406&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00075.2017
DO - 10.1152/ajprenal.00075.2017
M3 - Article
C2 - 29465304
AN - SCOPUS:85050810406
VL - 315
SP - F36-F44
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 1
ER -