Diabetic cystopathy is associated with PARP/JNK/ mitochondrial apoptotic pathway‐mediated bladder apoptosis

Abstract

Aims 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. Methods 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. Results 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. Conclusions 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. Neurourol. Urodynam. 29:1332–1337, 2010.