Online edition:ISSN 2758-089X

Pathological analysis of age-related bladder dysfunction

Introduction: Globally, over 50% of adults exhibit lower urinary tract symptoms. While aging is a known risk factor, the pathogenesis of age-related bladder dysfunction remains unclear. Recently, changes in oxidative stress were reported to be associated with the development of age-related bladder dysfunction; therefore, we examined the age-related changes in bladder function in an aging mouse model with a focus on oxidative stress. Materials and Methods: Experimental animals included male C57BL/6J mice aged 20, 40, 60, and 80 weeks. Using 20-week-old mice as the control group, age-related changes in bladder function were verified. Functional changes in the bladder were investigated using a pressure flow study (PFS), and morphohistological changes were analyzed using upright light microscopy and transmission electron microscopy (TEM). Additionally, changes in oxidative stress in the serum and bladder were analyzed using diacron-reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP) tests. The localization of oxidative stress in the bladder was analyzed using nitrotyrosine (NTY) and superoxide dismutase 2 (SOD2) immunofluorescence staining. Results: The PFS demonstrated significantly decreased maximum cystometric capacity and maximum detrusor pressure, as well as increased overcontraction of the bladder sphincter muscle and inadequate reduction in detrusor pressure after voiding with age. Masson’s trichrome staining and TEM showed thinning of the transitional epithelium of the bladder, and fibrosis extending from the interstitium to the muscle layer with age. The pixel area ratio of the epithelial layer significantly decreased, while that of the interstitial and muscular layers significantly increased with age in all layers (from epithelial to muscular layers). Oxidative stress analysis revealed a decrease in antioxidant capacity in the serum and bladder, followed by an increase in oxidative capacity, resulting in the overproduction of oxidative stress. Immunofluorescence staining showed that a biphasic decrease in antioxidant capacity (SOD2) preceded an increase in oxidative capacity (NTY) with aging. Analysis of the localization of oxidative stress in the bladder using immunofluorescence staining confirmed highly biphasic staining in the epithelial layer and from the interstitial to the muscular layer, and a biphasic decrease in SOD2 preceded an increase in NTY with aging. Conclusions: A biphasic state of oxidative stress in the bladder epithelial layer and from the interstitial to muscle layer, as well as bladder dysfunction causing a mixture of overactivity and underactivity of the detrusor muscle, were observed with aging. Oxidative stress is preceded by a decrease in antioxidant capacity, followed by an increase in oxidant capacity. These changes suggest that a decrease in antioxidant capacity may serve as a biomarker reflecting the pathology of early-stage age-related bladder dysfunction.

Nakatsuka T, et al