背景:高血糖诱发氧化应激导致糖尿病(DM)引起的排尿功能障碍。我们探索了抗氧化剂萝卜硫素,NF-E2相关的核因子-2(Nrf-2)激活剂,可以改善DM诱导的膀胱功能障碍。
方法:用链脲佐菌素诱导DM,并在诱导DM前给予萝卜硫素。用超灵敏化学发光分析仪测定膀胱活性氧(ROS)。线粒体功能指数线粒体Bax和胞质细胞色素c,抗氧化防御Nrf-2/HO-1,内质网应激标志物ATF-6/CHOP,通过Westernblot评估caspase3/PARP。
结果:DM增加Keap1,减少Nrf-2表达,与膀胱ROS增加相关,线粒体Bax易位,胞质细胞色素c释放,ATF-6/CHOP,膀胱caspase-3/PARP通过增加收缩间期和排尿时间导致排尿功能障碍。然而,萝卜硫素显著增加核Nrf-2/HO-1轴表达,减少膀胱ROS量,线粒体Bax易位,细胞色素c释放,ATF-6/CHOP和caspase3/PARP/凋亡,从而通过缩短的收缩间隔和排尿持续时间改善了排尿功能。
结论:我们建议萝卜硫素激活Nrf-2/HO-1信号保护线粒体功能并抑制DM诱导的ROS,内质网应激,细胞凋亡和排尿功能障碍。
BACKGROUND: Hyperglycemia evoked oxidative stress contributing to diabetes (DM)-induced voiding dysfunction. We explored whether antioxidant sulforaphane,a NF-E2-related nuclear factor erythroid-2 (Nrf-2) activator, may ameliorate DM-induced bladder dysfunction.
METHODS: DM was induced by streptozotocin and sulforaphanewas administered before DM induction.Bladder reactive oxygen species (ROS) were determined by an ultrasensitive chemiluminescence analyzer. Mitochondrial function index mitochondrial Bax and cytosolic cytochrome c, antioxidant defense Nrf-2/HO-1, endoplasmic reticulum stress marker ATF-6/CHOP, and caspase 3/PARP were evaluated by Western blot.
RESULTS: DM increased Keap1 and reduced Nrf-2 expression, associated with increase of bladder ROS, mitochondrial Bax translocation, cytosolic cytochrome c release, ATF-6/CHOP, caspase-3/PARP in bladders which resulted in voiding dysfunction by increased intercontraction intervals and micturition duration. However, sulforaphanesignificantly increased nuclear Nrf-2/HO-1axis expression, decreased bladder ROS amount, mitochondrial Bax translocation, cytochrome c release, ATF-6/CHOP and caspase 3/PARP/apoptosis, thereby improved the voiding function by the shortened intercontraction intervals and micturition duration.
CONCLUSIONS: We suggest that sulforaphanevia activating Nrf-2/HO-1 signaling preserved mitochondrial function and suppressed DM-induced ROS, endoplasmic reticulum stress, apoptosis and voiding dysfunction.