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Relaxin‐2 therapy reverses radiation‐induced fibrosis and restores bladder function in mice
Author(s) -
Ikeda Youko,
Zabbarova Irina V.,
Birder Lori A.,
Wipf Peter,
Getchell Samuel E.,
Tyagi Pradeep,
Fry Christopher H.,
Drake Marcus J.,
Kanai Anthony J.
Publication year - 2018
Publication title -
neurourology and urodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 90
eISSN - 1520-6777
pISSN - 0733-2467
DOI - 10.1002/nau.23721
Subject(s) - medicine , fibrosis , urology , relaxin , urinary bladder , radiation therapy , contractility , pathology , inflammation , detrusor muscle , interstitial cystitis , urinary system , receptor
Aim To determine the efficacy of human relaxin‐2 (hRLX2) in reversing radiation‐induced bladder fibrosis and lower urinary tract dysfunction (LUTD). Radiation cystitis is a consequence of radiotherapy for pelvic malignancies. Acutely, irradiation leads to reactive oxygen/nitrogen species in urothelial cells, apoptosis, barrier disruption, and inflammation. Chronically, this results in collagen deposition, bladder fibrosis, and attenuated storage and voiding functions. In severe cases, cystectomies are performed as current therapies do not reverse fibrosis. Methods We developed a mouse model for selective bladder irradiation (10 Gray; 1 Gy = 100 rads) resulting in chronic fibrosis within 6 weeks, with decreased bladder compliance, contractility, and overflow incontinence. Seven weeks post‐irradiation, female C57Bl/6 mice were continuously infused with hRLX2 (400 μg/kg/day/14 days) or vehicle (saline) via subcutaneous osmotic pumps. Mice were evaluated in vivo using urine spot analysis, cystometrograms and external urethral sphincter electromyograms; and in vitro using length‐tension measurements, Western blots, histology, and immunohistochemistry. Results hRLX2 reversed fibrosis, decreased collagen content, improved bladder wall architecture, and increased bladder compliance, detrusor smooth muscle Cav1.2 expression and detrusor contractility in mice with chronic radiation cystitis. hRLX2 treatment outcomes were likely caused by the activation of RXFP1/2 receptors which are expressed on the detrusor. Conclusion hRLX2 may be a new therapeutic option for rescuing bladders with chronic radiation cystitis.