Abstract: SA-PO618
Novel Drug Therapy to Prevent Bladder Fibrosis in a Pre-Clinical Model of Posterior Urethral Valves
Session Information
- Pediatric Nephrology - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1800 Pediatric Nephrology
Authors
- Cao, Kevin Xi, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Joannou, Maria K., UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Man, Cheuk Yan, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Johal, Navroop Singh, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Cuckow, Peter Malcom, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Fry, Christopher Henry, University of Bristol, Bristol, Bristol, United Kingdom
- Winyard, Paul, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- Long, David A., UCL Great Ormond Street Institute of Child Health, London, United Kingdom
Group or Team Name
- David Long - UCL Nephro-Urology
Background
Posterior Urethral Valves (PUV) remains one of the most severe paediatric conditions, responsible for most of the demand for renal replacement resources in childhood. We previously showed that excess extra-cellular matrix (ECM) in these bladders may be the pathologic culprit, so finding an anti-fibrotic therapy is a promising means to improve outcomes in this disorder. We performed a pre-clinical trial with both an animal model of PUV and human cell culture experiments with PUV bladder cells, treating both with soluble guanylate cyclase (sGC) modulators to explore the therapeutic potential of this family of drugs.
Methods
8-week old male C57 mice (n=36) were used to create a PUV-analogue surgical model, through partial-ligation of the urethra, which were then orally-administered sGC modulators for two out of three weeks of the experiment. Bladders were stained with picosirius red to allow evaluation of the smooth muscle to connective tissue ratio (SM:CTr). Biomechanical assessments of the stress-strain relationship from these bladders was measured to derive elastic modulus, or stiffness from the steady-state tension (measured in kilopascals, kPa).
Furthermore, primary cell cultures were established from children with PUV undergoing bladder surgery or kidney transplant and treated with the same drugs over a 7-day course to determine relative changes in both ECM proteins and changes to gene expression of ECM genes.
Results
Our animal model generated a PUV-like morphology, reducing SM:CTr from 1.2 in sham surgery to 0.5 in the model, indicating a greater ECM content (p<0.001), with increase in detrusor stiffness from 50kPa to 170kPa. Treatment with either sGC activator, cinaciguat or sGC stimulator, BAY 41-2272 (10mg/kg) kept both these variables in the same range as sham surgery (p<0.001).
Culture of detrusor in a pro-fibrotic 1% fetal bovine serum milieu resulted in a 20% increase in fibronectin protein and gene expression, compared to control milieu of 10% serum, relative to housekeeping gene/protein GAPDH. Treatment in 1% serum with BAY 41-2272 reduced expression of fibronectin protein by seven-fold and FN1 gene expression by 20%.
Conclusion
SGC modulation in an in vivo and in vitro model described here demonstrates prognosis-altering potential for this on-market drug in PUV.
Funding
- Private Foundation Support