Department of Urology, Seoul National University Hospital, Seoul National University, Seoul, Korea.
Neurourol Urodyn. 2010 Sep;29(7):1332-7. doi: 10.1002/nau.20869.
Diabetic cystopathy, a common complication of diabetes, is frequently associated with an increase in oxidative stress and apoptosis of the bladder. Poly(ADP-ribose) polymerase (PARP) is activated under such conditions of oxidative stress, and plays a critical role in cell apoptosis. The aim of this study was to investigate whether the activation of PARP and subsequent activation of c-Jun N-terminal kinase (JNK) and the mitochondrial apoptotic pathway are involved in the development of diabetic cystopathy.
Bladder function was assessed in a streptozotocin (STZ)-induced diabetic rat model with or without 3-aminobenzamide treatment, a PARP inhibitor. The degree of bladder apoptosis, expression of poly(ADP-ribose) (PAR) in the bladder, phosphorylated JNK, the levels of Bcl-2 and Bax, caspase 3 activity and nuclear translocation of the apoptotic inducing factor (AIF) from mitochondria were investigated.
Bladder dysfunction was significantly associated with an increase of bladder apoptosis, and a reduction of the Bcl-2/Bax ratio. In addition, the amount of PAR, phosphorylated JNK, caspase 3 activity, and nuclear translocation of AIF were significantly increased in the diabetic rats. Inhibition of PARP significantly suppressed activation of PARP, JNK and restored the Bcl-2/Bax ratio. Activation of caspase 3 and nuclear translocation of AIF were also significantly reduced by PARP inhibition. As a result, the bladder apoptosis was attenuated and the bladder function improved.
These results indicate that bladder apoptosis is involved in diabetic cystopathy via activation of the PARP/JNK/mitochondrial apoptotic pathway. These findings may be used to develop novel therapies for patients with diabetic bladder dysfunction.
糖尿病性膀胱病是糖尿病的一种常见并发症，常伴有氧化应激和膀胱细胞凋亡增加。多聚（ADP-核糖）聚合酶（PARP）在这种氧化应激条件下被激活，并在细胞凋亡中发挥关键作用。本研究旨在探讨PARP 的激活以及随后 c-Jun N 端激酶（JNK）和线粒体凋亡途径的激活是否参与糖尿病性膀胱病的发生。
采用链脲佐菌素（STZ）诱导的糖尿病大鼠模型，观察 3-氨基苯甲酰胺（PARP 抑制剂）处理前后膀胱功能的变化。检测膀胱细胞凋亡程度、膀胱内多聚（ADP-核糖）（PAR）的表达、磷酸化 JNK、Bcl-2 和 Bax 的水平、caspase 3 活性以及凋亡诱导因子（AIF）从线粒体的核易位。
膀胱功能障碍与膀胱细胞凋亡增加和 Bcl-2/Bax 比值降低显著相关。此外，糖尿病大鼠的 PAR、磷酸化 JNK、caspase 3 活性和 AIF 的核易位明显增加。PARP 抑制剂显著抑制了 PARP、JNK 的激活，并恢复了 Bcl-2/Bax 比值。PARP 抑制也显著降低了 caspase 3 的激活和 AIF 的核易位。结果，膀胱细胞凋亡减少，膀胱功能得到改善。
这些结果表明，通过激活 PARP/JNK/线粒体凋亡途径，膀胱细胞凋亡参与了糖尿病性膀胱病。这些发现可能用于开发治疗糖尿病膀胱功能障碍的新疗法。
