Metabolic Syndrome, Bladder Ischemia and Lower Urinary Tract Symptoms: The Epidemiological Evidences and Pathophysiological Mechanisms

• Main Authors: Huai-Ching Tai, 戴槐青
• Other Authors: 余宏政
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/37z34c

博士 === 國立臺灣大學 === 臨床醫學研究所 === 105 === Background Lower urinary tract symptoms (LUTS) and metabolic syndrome (MS) are both highly prevalent public health problems, especially in the elderly population. Many recent epidemiological evidences have shown that MS is one of the possible factors for the development of LUTS. In the Third National Health and Nutrition Examination Survey conducted on men > 60 years, the risks of having LUTS increased significantly in men with ≥ 3 MS components when compared with their control counterparts (OR 1.80; 95% CI 1.11–2.94). Men with MS also had a higher growth rate of prostate versus men without MS. Several mechanisms between LUTS and MS have been proposed, including endothelial dysfunction, autonomic hyperactivity, upregulation of Rho-kinase and pelvic atherosclerosis. In addition to common diabetic complications such as nephropathy, neuropathy and retinopathy, diabetic patients are also predisposed to LUT dysfunction, leading to bothersome LUTS, especially the overactive bladder (OAB). However, the clinical manifestations of diabetic LUT dysfunction are mixed, and may progress into end stage bladder disease, resulting in chronic retention, urinary tract infection and kidney damage. Although the association between diabetes and LUT dysfunction is evident, it is still not well known about its risk factors. Based on the fact that MS is common among patients with diabetes, it is of interest to investigate whether MS plays a critical role in the development of LUTS in women with diabetes. This thesis contains 2 studies. The goal of the first part (an epidemiological study) is to evaluate the role of MS in the development of LUTS/OAB in women with diabetes. The goal of the second part (a basic research) is to study the underlying mechanisms of ischemia-induced bladder dysfunction and explore the possible therapeutic agents for this entity. Materials and methods The first part is a cross-sectional epidemiological study. From October 2005 to June 2007, a total of 518 women with type 2 diabetes were enrolled in our study. Their clinical data including medical history, biochemical tests, physical examination and questionnaire results for LUTS were collected. All patients were divided into 2 groups as diabetes with MS group and diabetes without MS group, according to the definition of MS by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). LUT function were evaluated with the American Urological Association Symptom Index (AUA-SI), Indevus Urgency Severity Scale (IUSS) questionnaire and uroflowmetry, respectively. We analyzed the data of these two groups with statistical methods. The second part is a basic research, which is divided into three phases. In the first phase, we established the animal model of ischemia-induced bladder dysfunction by bilateral partial arterial occlusion (BPAO) in rat. In the second phase, we sought to investigate the molecular mechanism of the ischemia-induced bladder dysfunction. In the third phase, we examined the effectiveness of therapeutic agents, including a muscarinic receptor antagonist, a purinergic receptors antagonist and a Nrf2 activator sulforaphane. Results In our epidemiological study, diabetic women with MS had significantly higher storage and total AUA-SI scores as well as a higher prevalence of LUTS/OAB. Most intriguingly, the number of MS components was strongly associated with the LUTS severity and OAB prevalence. Multivariate analysis revealed that peripheral neuropathy, but not MS, significantly predicted LUTS/OAB in diabetic women after age adjustment. However, MS remained significantly predictive for LUTS after additional adjustment for neuropathy. In the experimental study, the animal model of bladder ischemia was successfully established by BPAO in rats. We found that BPAO significantly induced the presence of oxidative stress and upregulated the expressions of several molecular reactions including endoplasmic reticulum stress (GRP78/CHOP), autophagy (Beclin-1/p62/LC3 II) and apoptosis (caspase 3). BPAO also disturbed the Keap1-Nrf2 pathways. The most importantly, BPAO altered bladder neurotransmission by upregulating muscarinic and purinergic signaling, which might be the main cause of ischemia-induced bladder dysfunction. Treatment with a muscarinic or purinergic receptor antagonist was failed to restore bladder function. On the other hand, sulforaphane effectively attenuated ischemia-associated cellular responses in the bladder, subsequently ameliorated ischemia-induced bladder dysfunction and might emerge as a novel strategy to protect the bladder against ischemia-induced oxidative damage. Conclusions We hypothesize that diabetic peripheral neuropathy is the most important predictor for the development of LUTS in women with type 2 diabetes. However, the presence of MS components may compound the risks of LUTS through atherosclerosis and subsequent bladder ischemia. Our animal model of ischemic bladder further confirms our hypothesis. Ischemia not only increases the expressions of oxidative stress and associated cellular responses, but also affects the bladder neurotransmission pathways, resulting in bladder dysfunction. Treatment with Nrf2 activator sulforaphane is able to attenuate the ischemia-induced bladder dysfunction effectively.