Diabetic cystopathy is associated with PARP/JNK/mitochondrial apoptotic pathway-mediated bladder apoptosis.
OBJECTIVE
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.
Li
Wen Ji
WJ
Department of Urology, Seoul National University Hospital, Seoul National University, Seoul, Korea.
Oh
Seung-June
SJ
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D048909:Diabetes Complications / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001745:Urinary Bladder Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D014563:Urodynamics; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; C494828:Bax protein, rat; D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3