PROJECT SUMMARY
The overall goal of this project is to examine the role of oxidative stress in the pathogenesis of
urinary incontinence (UI), including urge UI (overactive bladder /detrusor overactivity) and stress
UI, in obesity/pre-type 2 diabetes mellitus (O/pre-T2DM). Obese and/or type 2 diabetic
individuals, especially women, are at a substantial risk of developing UI. Furthermore, obesity
and T2DM are strongly associated with systemic oxidative stress and inflammation. We
previously discovered that, in rodent models of type 1 diabetes, bladder dysfunction follows a
temporal course of progression from a compensated to a decompensated phase. More recently,
we and others have begun to uncover a different natural history of UI in obesity and T2DM, but
the time course and mechanisms of UI phenotypes associated with those conditions remain
unknown. Now we propose to study mechanisms of UI in O/pre-T2DM by taking advantage of
our two newly developed animal models, conditional smooth muscle-specific Sod2 knockout
mice and mice with simulated birth trauma, as well as a new technique to measure bladder
sensation in mice. Based on our current observations, we hypothesize that: 1) UI in O/pre-
T2DM is mediated by obesity-associated increased oxidative stress and can be alleviated by
antioxidant treatment, and 2) stress UI in O/pre-T2DM requires an additional insult such as
vaginal delivery/birth trauma. We will test our hypotheses via two Specific Aims: In SA #1, we
will assess the pathogenesis of detrusor overactivity in male and female C57BL/6 mice with high
fat diet (HFD)-induced obesity, with or without treatment with the antioxidant MitoQ, and in HFD-
fed male and female C57BL/6 mice with conditional smooth muscle specific deletion of the
manganese superoxide dismutase gene (Sod2-/- mice), relative to lean controls. Assays will
include conscious cystometry, contractile responses of bladder detrusor strips, neuroselective
measurement of bladder sensation, and a novel MRI acquisition and image analysis technique
to assess body lipid burden. In SA #2, we will assess recovery from vaginal distension-induced
stress UI in HFD-fed, female obese female mice with or without MitoQ treatment, and in HFD-
fed, female obese Sod2-/- mice, relative to lean controls, using measurements of leak point
pressure, urethral morphology and innervation, and body lipid burden. Successful completion of
these studies will provide critical leads for prevention and therapy of UI in O/pre-T2DM.