title: Quantitative Proteomic Analysis of Differentially Expressed Proteins and Downstream Signaling Pathways in Chronic Bladder Ischemia.
abstract: OBJECTIVE
  Growing evidence suggests that ischemia may contribute to aging associated bladder dysfunction and lower urinary tract symptoms. Our goal was to determine the effects of chronic ischemia on bladder proteomic profiles and characterize downstream signaling pathways.
  
  
  METHODS
  Bilateral iliac artery atherosclerosis and chronic bladder ischemia were created in male Sprague Dawley® rats. At 8 weeks cystometrograms were obtained. Ischemic and control bladder tissues were then processed for label-free quantitative proteomic analysis. GO (Gene Ontology) and IPA (Ingenuity® Pathway Analysis) software were used to classify altered proteins in bladder ischemia. Western blot was done to confirm differentially expressed proteins. Tissue structure was examined by transmission electron microscopy.
  
  
  RESULTS
  Chronic ischemia resulted in detrusor instability and noncompliance. Proteomic analysis revealed a total of 4,277 proteins in ischemic and 4,602 in control bladder tissues. In ischemic bladders 359 and 66 proteins were differentially expressed with a greater than twofold and fivefold change, respectively. On GO analysis differentially expressed proteins were associated with molecular signaling mechanisms underlying proteolysis and degenerative processes. Pathway and network analysis of ischemic tissues suggested that altered proteins are involved in ubiquitination, Nrf2 mediated oxidative stress response, cell death, glucose metabolism and cytoskeleton remodeling. Western blot verified changes in 4 representative proteins, including Nedd4l, Mpo, Ca3 and Fkbp5. Altered proteomic profile of the bladder was associated with widespread ultrastructural damage.
  
  
  CONCLUSIONS
  Alterations of bladder proteomic profiles in ischemia may provide new insight into molecular pathways underlying bladder dysfunction and lower urinary tract symptoms in pelvic atherosclerosis.
authors.affiliation: Departments of Urology, Surgery, Pathology and Proteomics Laboratory, Veterans Affairs Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Su
authors.affiliation: Departments of Urology, Surgery, Pathology and Proteomics Laboratory, Veterans Affairs Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Han-Pil
authors.initials: HP
authors.lastname: Choi
authors.affiliation: Cancer Research Center, Shandong University School of Medicine, Jinan, People's Republic of China.
authors.forename: Fengqin
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Xi'an Tangdu Hospital, Xi'an, People's Republic of China.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. Electronic address: zhoufei@fmmu.edu.cn.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
authors.affiliation: Departments of Urology, Surgery, Pathology and Proteomics Laboratory, Veterans Affairs Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts. Electronic address: jyang@bu.edu.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Departments of Urology, Surgery, Pathology and Proteomics Laboratory, Veterans Affairs Boston Healthcare System and Boston University School of Medicine, Boston, Massachusetts. Electronic address: kazadzoi@bu.edu.
authors.forename: Kazem M
authors.initials: KM
authors.lastname: Azadzoi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D007511:Ischemia / Q000503:physiopathology*; D059411:Lower Urinary Tract Symptoms / Q000503:physiopathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D040901:Proteomics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D001743:Urinary Bladder / Q000503:physiopathology*
keywords: atherosclerosis; ischemia; lower urinary tract symptoms; proteomics; urinary bladder