李懿倫^1,2、吳炳男^2,3、莊淑棉⁴、吳文正^2,5,7、阮雍順^2,6,7

¹衛生福利部新營醫院泌尿科；²高雄醫學大學醫學院醫學研究所，³藥學部，⁴醫學研究部癌症中心轉譯研究中心；⁵高雄市立大同醫院泌尿科；⁶高雄市立小港醫院泌尿科；

⁷高雄醫學大學附設醫院泌尿科

Yi-Lun LEE^1,2, Bin-Nan Wu^2,3, Shu-Mien Chuang⁴, Wen-Jeng Wu^2,5,7 , Yung-Shun Juan^2,6,7

Department of Urology, Sinying Hospital, Ministry of Health and Welfare, Tainan, Taiwan¹； Graduate Institute of Medicine² and Department of Pharmaology³ College of Medicine, and Translational Research Center⁴, Cancer Center, Department of Medical Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital⁵；Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital⁶；Department of Urology, Kaohsiung Medical University Hospital⁷, Kaohsiung, Taiwan

 

Purpose: Our study attempted to elucidate the mechanism of epigallocatechin-3-gallate (EGCG) modulating oxidative stress in a rat model of metabolic syndrome (MetS) and menopause-associated overactive bladder (OAB). We also evaluated the possible effects of EGCG on the metabolic dysfunction and menopausal related bladder over-activity by investigating the expressions of oxidative markers and mitochondria respiratory enzyme complexes in the bladders.

Materials and Methods: Female Sprague-Dawley rats were divided into five experimental groups. These five groups included: (a) the control group (with normal chow diet), (b) the MetS group (with high fat and high sugar (HFHS) diet), (c) the MetS+menopause group (receiving surgical menopause and HFHS diet), (d) the MetS+menopause+EGCG group (receiving surgical menopause and HFHS diet plus EGCG injection) and (e) the MetS+EGCG group (with HFHS diet plus EGCG injection). In each group, cystometry and metabolic cage micturition pattern study were performed to evaluate the bladder function. Physical indicator, and biochemistry parameters were measured monthly for six months. The terminal deoxynucleotidyl transferase (dUTP) nick-end labeling (TUNEL) assay was used to determine the distribution of apoptotic cells. The expressions of oxidative markers and mitochondrial respiratory enzymes were assessed by Western blots.

Results: The rats fed with HFHS diet would develop metabolic dysfunctions in physical indicators and biochemical parameters, and overactive bladder presentations in cystometry and metabolic cage study. Additionally, the rats fed with HFHS diet plus surgical menopause would deteriorate the changes of metabolic dysfunction and bladder hyperactivity. Masson’s stains exhibited the overexpression of inflammatory and fibrosis markers in the MetS and MetS+menopause groups, while the administration of EGCG alleviated the inflammatory and fibrotic process in the bladders. The expressions of DNP and nitrotyrosine, the oxidative markers, and mitochondrial enzyme complexes subunits were significantly increased in the MetS and MetS+menopause groups. The TUNEL staining results indicated that metabolic syndrome and menopause-associated bladder apoptosis was related to mitochondria pathway and EGCG could modulate oxidative stress through mitochondria-mediated mechanism. These findings supported the proposal that oxidative stress mediated by mitochondria and ER was involved in surgical menopause and HFHS diet - induced metabolic syndrome.

Conclusions: The metabolic syndrome and menopause enhanced the expressions of oxidative markers in the bladder and mitochondria respiratory enzyme complexes, leading to inducing oxidative stress and increasing bladder apoptosis and interstitial fibrosis. The increased oxidative stress and its accompanied apoptosis and mitochondrial dysfunction wound be critical factors underlying metabolic syndrome and menopause related bladder over-activity and inflammatory process, whereas antioxidant EGCG offered a beneficial effect on lessening oxidative damages through mitochondria-mediated pathway.