A MAPP Network Study: Overexpression of Tumor Necrosis Factor-α in Mouse Urothelium Mimics Interstitial Cystitis.

Interstitial cystitis/ bladder pain syndrome (IC/BPS) 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 upon 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 wild type. 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 afferents 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 novel model for characterizing mechanisms of IC symptoms and evaluating therapies.

American journal of physiology. Renal physiology. 2018 Feb 21 [Epub ahead of print]

Wenbin Yang, Timothy J Searl, Ryan E Yaggie, Anthony J Schaeffer, David J Klumpp

Urology, Northwestern University, United States., Molecular Pharmacology & Biological Chemistry, Northwestern University Medical School, United States.