Cao, Kevin Xi; (2024) Targeting fibrosis as a treatment for Posterior Urethral Valves. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Posterior urethral valves (PUV) is a severe developmental urinary tract disorder. The obstructing valves are correctable with surgery, but this does not reverse the persistence and progression of bladder dysfunction, which can result in end-stage kidney disease. Understanding this dysfunction and finding routes to treat it may improve the prognosis of PUV. I hypothesised that the degree of deposition of extra-cellular matrix (fibrosis) was linked to the severity of bladder dysfunction in PUV and a potential therapeutic target to improve bladder function. Hence, the primary aim of my thesis was to evaluate the extent of fibrosis and magnitude of bladder dysfunction in PUV. The secondary aim was to evaluate the potential anti-fibrotic effects of a novel family of drugs, the soluble guanylate cyclase (sGC) modulators, in ameliorating the pathology seen in PUV bladders. I performed: (i) histological and physiological evaluations of PUV bladder specimens compared with specimens from children with normal functioning bladders, and other congenital bladder disorders; (ii) the generation of a small-rodent model to mimic PUV, which was treated with sGC modulators and (iii) treatment of cell cultures established from PUV bladders with sGC modulators. PUV specimens were more fibrotic and stiffer than normal bladder and comparatively more severe than specimens obtained from other congenital lower urinary tract conditions. In both a short preventative dosing experiment and a long interventional course, the sGC stimulator BAY 41-2272 improved the histological and physiological changes seen in the mouse model. The sGC activator cinaciguat had potent effects on bladder physiology but not on its histology. Cell cultures from PUV patients, responded to sGC modulators in reducing their expression of pro-fibrotic genes and proteins. Collectively, this research highlights the relationship between bladder fibrosis and function in PUV and demonstrates the potential for its treatment with a new family of anti-fibrotic drugs.

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