| Popis: |
Jing-Hua Yang,1 Zuohui Zhao,2 Wanting Niu,3 Han-Pil Choi,3 Kazem M Azadzoi4 1Department of Surgery, Boston University School of Medicine and Proteomics Laboratory, VA Boston Healthcare System, Boston, MA, USA; 2Department of Urology, Boston University School of Medicine, Boston, MA, USA; 3Research Department, VA Boston Healthcare System, Boston, MA, USA; 4Departments of Urology and Pathology, VA Boston Healthcare System and Boston University School of Medicine, Boston, MA, USACorrespondence: Kazem M Azadzoi, VA Boston Healthcare System, Building 1A, Room 317 (151), 150 South Huntington Avenue, Boston, MA, 02130, USA, Tel +1 857-364-5602, Email kazadzoi@bu.eduPurpose: Growing evidence suggests that ischemia provokes detrusor overactivity and degenerative responses in the bladder. Underlying mechanisms appear to involve modification of smooth muscle contractile rudiments by hypoxia, redox, cellular stress and cell survival signaling. Downstream pathways of cellular stress and stress response molecules eliciting bladder dysfunction in ischemia remain largely elusive. Our goal was to define the role of double stranded RNA (dsRNA), a stress response molecule provoked by redox, in ischemia mediated bladder dysfunction.Methods: A rat model of pelvic ischemia along with a cell culture hypoxia model were used to investigate the expression levels, functional consequences, structural aspects, and regulatory mechanisms of dsRNA in the bladder. Gene and protein expression were examined by reverse transcription polymerase chain reaction (RT-PCR), dot blot, and Western blotting, respectively. Tissue structure and function were assessed using histological staining and organ bath. Regulatory mechanisms were analyzed in cultured bladder smooth muscle cells.Results: The data presented here provide the first evidence of the formation of dsRNA in the overactive bladder. dsRNA is a cellular stress response molecule that sensitizes smooth muscle and regulates inflammatory and degenerative rejoinders. Our data suggest that the production of dsRNA in the bladder is provoked by ischemia. Formation of dsRNA appears to augment bladder smooth muscle contractions and provoke fibrotic and apoptotic responses. Downstream actions of dsRNA in the bladder may involve upregulation of dsRNA-activated protein kinase R (PKR) and caspase-3, the executioner of apoptosis.Conclusion: Activation of dsRNA/PKR pathway may play a role in sensitization of bladder smooth muscle cells to contractile stimuli, whereas dsRNA and caspase-3 crosstalk appear to modulate cellular stress and instigate degenerative responses in bladder ischemia. These observations suggest the role of dsRNA in bladder dysfunction and may open new perspectives to overcome overactive smooth muscle contractions and structural damage in the bladder.Keywords: bladder, ischemia, overactivity, dsRNA, contraction, degeneration |
