Aging-Associated Changes in Oxidative Stress Negatively Impacts the Urinary Bladder Urothelium
2
조회
0
다운로드
4
인용
0
참고문헌
키워드
초록
Purpose: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the harsh chemical composition of urine, and exhibits signaling properties via the release of mediators within the bladder wall that affect bladder functioning. Aging is associated with detrimental changes in cellular health, in part by increasing oxidative stress in the bladder mucosa, and more specifically the urothelium. This, in turn, may impact urothelial mitochondrial health and bioenergetics. Methods: We collected mucosal tissue samples from both young (3–4 months old) and aged (25–30 months old) rats. Tissue was evaluated for p21-Arc, nitrotyrosine, and cytochrome C expression by western immunoblotting. Urothelial cells were cultured for single-cell imaging to analyze basal levels of reactive oxygen species and the mitochondrial membrane potential. Mitochondrial bioenergetics and cellular respiration were investigated by the Seahorse assay, and measurements of adenosine triphosphate release were made using the luciferin-luciferase assay. Results: Aging was associated with a significant increase in biomarkers of cellular senescence, oxidative stress, and basal levels of reactive oxygen species. The mitochondrial membrane potential was significantly lower in urothelial cell cultures from aged animals, and cultures from aged animals showed a significant decrease in mitochondrial bioenergetics. Conclusions: Aging-related increases in oxidative stress and excessive reactive oxygen species may be contributing factors underlying lower urinary tract symptoms in older adults. The mechanisms outlined in this study could be utilized to identify novel pharmaceutical targets to improve aging-associated bladder dysfunction.
Abstract
Purpose: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the harsh chemical composition of urine, and exhibits signaling properties via the release of mediators within the bladder wall that affect bladder functioning. Aging is associated with detrimental changes in cellular health, in part by increasing oxidative stress in the bladder mucosa, and more specifically the urothelium. This, in turn, may impact urothelial mitochondrial health and bioenergetics. Methods: We collected mucosal tissue samples from both young (3–4 months old) and aged (25–30 months old) rats. Tissue was evaluated for p21-Arc, nitrotyrosine, and cytochrome C expression by western immunoblotting. Urothelial cells were cultured for single-cell imaging to analyze basal levels of reactive oxygen species and the mitochondrial membrane potential. Mitochondrial bioenergetics and cellular respiration were investigated by the Seahorse assay, and measurements of adenosine triphosphate release were made using the luciferin-luciferase assay. Results: Aging was associated with a significant increase in biomarkers of cellular senescence, oxidative stress, and basal levels of reactive oxygen species. The mitochondrial membrane potential was significantly lower in urothelial cell cultures from aged animals, and cultures from aged animals showed a significant decrease in mitochondrial bioenergetics. Conclusions: Aging-related increases in oxidative stress and excessive reactive oxygen species may be contributing factors underlying lower urinary tract symptoms in older adults. The mechanisms outlined in this study could be utilized to identify novel pharmaceutical targets to improve aging-associated bladder dysfunction.
참고문헌 (28)
- Irwin DE, "Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries:results of the EPIC study", Eur Urol, 50, pp.1306~1314 (2006)
- Linde JM, "Urinary incontinence in the Netherlands : prevalence and associated risk factors in adults", Neurourol Urodyn, 36, pp.1519~1528 (2017)
- Gibson W, "Incontinence in the elderly, ‘normal’ ageing, or unaddressed pathology?", Nat Rev Urol, 14, pp.440~448 (2017)
- Suskind AM, "The aging overactive bladder : a review of aging-related changes from the brain to the bladder", Curr Bladder Dysfunct Rep, 12, pp.42~47 (2017)
- Diokno AC, "Prevalence of urinary incontinence and other urological symptoms in the noninstitutionalized elderly", J Urol, 136, pp.1022~1025 (1986)
- Fry CH, "The role of the mucosa in normal and abnormal bladder function", Basic Clin Pharmacol Toxicol, 119(Suppl 3), pp.57~62 (2016)
- Hanna-Mitchell AT, "Non-neuronal acetylcholine and urinary bladder urothelium", Life Sci, 80, pp.2298~2302 (2007)
- Birder LA, "Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder", Am J Physiol, 275, pp.F226~9 (1998)
- Ferguson DR, "ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes--a possible sensory mechanism", J Physiol, 505(Pt 2), pp.503~511 (1997)
- Birder L, "Urothelial signaling", Physiol Rev, 93, pp.653~680 (2013)
- Birder LA, "How does the urothelium affect bladder function in health and disease? ICI-RS 2011", Neurourol Urodyn, 31, pp.293~299 (2012)
- Birder LA, "Mechanisms of disease: involvement of the urothelium in bladder dysfunction", Nat Clin Pract Urol, 4, pp.46~54 (2007)
- Cadenas E, "Mitochondrial free radical generation, oxidative stress, and aging", Free Radic Biol Med, 29, pp.222~230 (2000)
- Lee J, "Reactive oxygen species, aging, and antioxidative nutraceuticals", Compr Rev Food Sci Food Saf, 3, pp.21~33 (2004)
- Andersson KE, "Oxidative stress and its possible relation to lower urinary tract functional pathology", BJU Int, 121, pp.527~533 (2018)
- Birder LA, "Is there a role for oxidative stress and mitochondrial dysfunction in age-associated bladder disorders?", Ci Ji Yi Xue Za Zhi, 32, pp.223~226 (2020)
- Perše M, "Oxidative status and lipofuscin accumulation in urothelial cells of bladder in aging mice", PLoS One, 8, pp.e59638~ (2013)
- Birder LA, "The aging bladder insights from animal models", Asian J Urol, 5, pp.135~140 (2018)
- Truschel ST, "Primary uroepithelial cultures. A model system to analyze umbrella cell barrier function", J Biol Chem, 274, pp.15020~15029 (1999)
- Kullmann FA, "Heterogeneity of muscarinic receptor-mediated Ca2+ responses in cultured urothelial cells from rat", Am J Physiol Renal Physiol, 294, pp.F971~81 (2008)
- Chen L, "NLRP3", IL1β inflammasome associated with the aging bladder triggers bladder dysfunction in female rats, 2019, pp.19, 2960~2968
- Hudgins AD, "Ageand tissue-specific expression of senescence biomarkers in mice", Front Genet, 9, pp.59~ (2018)
- Shie JH, "Increased cell apoptosis of urothelium mediated by inflammation in interstitial cystitis", painful bladder syndrome, 2012, pp.79, 484.e7~484.e13
- Rüb C, "Mitochondrial quality control by the Pink1", Parkin system, 2017, pp.367, 111~123
- Birder LA, "Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions", JCI Insight, 5, pp.e140109~ (2020)
- Green DR, "Mitochondria and apoptosis", Science, 281, pp.1309~1312 (1998)
- Frank S, "The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis", Dev Cell, 1, pp.515~525 (2001)
- Birder LA, "A uro-protective agent with restorative actions on urethral and striated muscle morphology", World J Urol, 39, pp.2685~2690 (2021)