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Investigating the pathogenesis of urinary bladder dysfunction in experimental diabetes mellitus
[Thesis]. Manchester, UK: The University of Manchester; 2019.
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Abstract
People with diabetes mellitus (DM) have an increased risk of developing secondary complications, which includes diabetic cystopathy - dysfunction of the urinary bladder that can negatively impact on health and quality of life. The aetiology of diabetic cystopathy is not well understood, particularly in late stage. The aim of this project was to elucidate the underlying pathogenesis of diabetic cystopathy in rats with up to 16 weeks of experimental DM. We hypothesised that the impact of experimental diabetes (with associated polyuria) on the urinary bladder is different to that of non-diabetic rats with polyuria. We studied rats with streptozotocin (STZ)â€Â“induced DM and rats administered 5% sucrose in their drinking water (polyuria controls) over 16 weeks to investigate the impact of increased fluid consumption (with and without DM ) on the urinary bladder compared with age-matched (non-diabetic) control male Wistar rats. Polydipsia and significant bladder enlargement was observed in both the diabetic and sucrose-treated rats. There was significant hypertrophy of detrusor smooth muscle cells in both the diabetic and sucrose-treated rats, and a loss of collagen in the detrusor muscle and lamina propria layers with an increase in the average size of peripherin-immunoreactive nerve bundles within the urinary bladder of diabetic compared to control rats. Interestingly, there were no significant changes in collagen in the sucrose-treated rats compared to age-matched control rats, indicating the changes the extracellular matrix may be a result of the metabolic impact of diabetes rather than the polyuria-induced remodelling. Since collagen fibrils play an important role in the micturition cycle, providing tensile strength for the expanding and contacting bladder, we investigated the micromechanical properties of the bladder using localized atomic force microscopy indentation of ex vivo tissue cryosections. We found the detrusor muscle in diabetic rats was significantly softer than the bladder from control or sucrose-treated rats, and hypothesized that this may contribute to increased compliance and/or inadequate emptying of the bladder in diabetic cystopathy. RNA was extracted from the bladders of STZ-diabetic, sucrose-treated or untreated rats and processed by Affymetrix microarray and bioinformatics followed by realtime PCR and immunocytochemical analysis. Ingenuity pathway analysis (IPA) and heatmap visualization and cluster analysis integrated the datasets and identified differentially-expressed genes and over-represented pathways. Interestingly, IPA analysis revealed significant dysregulation of 45 pathways in the bladders of STZ-diabetic rats (16 weeks post-STZ) compared with age-matched controls, which included 'Axonal guidance signalling and â€Â˜Inhibition of Matrix Metalloproteinase' pathways, not overrepresented in IPA analysis of changes in the sucrose-treated rat bladders. We provide a detailed molecular description of the distinct differences that occur during bladder remodelling in experimental DM compared to non-diabetic rats with polyuria, and suggest that future studies, targeting the neuropathic and collagen changes in DM may be valuable in improving bladder function in diabetic cystopathy.