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Role of Interstitial Cells in Diabetic Bladder Dysfunction
Diabetic bladder dysfunction (DBD) is the most common and costly complications of Diabetes Mellitus (DM). Estimates of the prevalence of DBD range from 25% to 83%. DM causes the bladder to undergo 2 phases of alterations. Early phase DBD manifests as storage problems such as urgency and urge incontinence at the clinical level. Late phase DBD manifests as voiding problems, leading to bladder inability to empty. The pathophysiology of overactive bladder of early phase DBD is due to increased phasic activity in the bladder smooth muscle of animal models and patients with detrusor overactivity. However the exact pathophysiological mechanism of increased detrusor responsiveness in early stage DBD is divergent and unclear. In this proposal we will focus on the changes in function and phenotype of detrusor smooth muscle to understand the mechanism of early DBD. We will use two types of animal models, streptozotocin (STZ)-induced type 1DM and high fat-diet induced type 2 DM mice. We have recently discovered a novel type of interstitial cells in detrusor muscles. These cells were identified with antibodies against platelet-derived growth factor receptor-alpha ?(PDGFRa). PDGFRa+ cells have been identified in human, guinea pig and murine detrusor muscle. PDGFRa+ cells are associated with varicose nerve processes in detrusor muscles5. Thus, PDGFRa+ cells may be innervated and receive and transduce neurotransmitters. small-conductance Ca2+-activated K+ (SK) channels are known to be involved in membrane stabilization in the detrusor. SK channels were reported in detrusor smooth muscle cells (SMCs). However, the current density attributable to SK channels in detrusor SMC is minimal. In contrast, PDGFRa+ cells display a very high current density attributable to SK channels. Defects of SK channels in PDGFRa+ cells amplify contractile responses leading to a detrusor overactivity phenotype. Thus, we will characterize the molecular and protein components of these novel PDGFRa+ cells and determine how these cells participate in the regulation of DBD. The results will provide information about the function of PDGFRa+ cells in the detrusor and serve as a baseline for evaluations of function and plasticity of these cells in early stage DBD.

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