Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice

Youko Ikeda, Irina V. Zabbarova, Lori A. Birder, Peter Wipf, Samuel E. Getchell, Pradeep Tyagi, Christopher H. Fry, Marcus J. Drake, Anthony J. Kanai*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

12 Citations (Scopus)
177 Downloads (Pure)

Abstract

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 (400μg/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.

Original languageEnglish
Number of pages11
JournalNeurourology and Urodynamics
Early online date28 May 2018
DOIs
Publication statusE-pub ahead of print - 28 May 2018

Structured keywords

  • Centre for Surgical Research

Keywords

  • Cav1.2
  • Fibrosis
  • Human relaxin-2 (hRLX2)
  • Matrix metalloproteases (MMPs)
  • Radiotherapy

Fingerprint Dive into the research topics of 'Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice'. Together they form a unique fingerprint.

Cite this