title: Diabetic cystopathy is associated with PARP/JNK/mitochondrial apoptotic pathway-mediated bladder apoptosis.
abstract: 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.
authors.affiliation: Department of Urology, Seoul National University Hospital, Seoul National University, Seoul, Korea.
authors.forename: Wen Ji
authors.initials: WJ
authors.lastname: Li
authors.forename: Seung-June
authors.initials: SJ
authors.lastname: Oh
mesh_terms: 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
chemical_list: 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