Molecular Characterization of Detrusor Interstitial Cells in Diabetic Detrusor Overactivity
Diabetic detrusor overactivity is the most common and costly complication of Diabetes Mellitus (DM). Estimates of the prevalence of diabetic bladder dysfunction range from 25% to 83%. DM causes two phases of change in bladder function: In the early phase of DM, detrusor overactivity is observed, but later stage of DM shows underactive bladder in animal models and human patients. Many tissue-level studies have been performed to investigate the mechanisms of diabetic bladder dysfunction, but these mechanisms remain unclear at present. We have found a novel type of interstitial cell in detrusor muscles of the bladder recently. These cells were first identified with antibodies against platelet-derived growth factor receptor-a (PDGFRa), and we refer to them by this chemical coding, PDGFRa+ cells. Detrusor PDGFRa+ cells are an important mechanosensitive element that is activated during bladder filling. These cells show high expression of TRPV4 channels and small conductance Ca2+-activated K+ (SK) channels in comparison to smooth muscle cells (SMCs) which have minimal expression of both channels. During bladder filling activation of TRPV4 channels increases Ca2+ influx into PDGFRa+ cells and this activates SK channels, leading to stabilization of membrane potential in the SMC/PDGFRa+ cell syncytium. In this project, we will focus on exploring molecular mechanisms of early diabetic detrusor overactivity. We will target specific cellular mechanisms to explain the early phases of diabetic detrusor overactivity. The overarching hypotheses of this project are that changes in membrane excitability-regulating genes of PDGFRa+ cells and loss of PDGFRa+ cells of diabetic detrusor muscles induce detrusor overactivity due to disruption of membrane stabilization during filling. The project is novel and timely because: i) PDGFRa+ cells have recently been discovered and nothing is known about their fate in DM; ii) cellular remodeling of detrusor muscles has never been characterized in DM. Molecular characterization of the changes in PDGFRa+ cells in DM bladder will provide new ideas about the etiology of diabetic bladder dysfunction and may identify new rationales for therapies.

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