AB294. SPR-21 Sex differences in bladder dysfunction in response to enteric neuronal NFκB overactivation and experimentally induced colitis in mice

OBJECTIVE: In experimental models, animals with induced colitis have increased urinary frequency and abnormalities in bladder contraction to cholinergic and electric field stimulation (EFS). Nuclear factor kappa B (NFκB) is a major mediator of the inflammatory response in inflammatory bowel disease and syndrome. The aim of the present study was to determine the effect of increased NFκB signalling in enteric neurons on bladder contraction with and without experimentally induced colitis. METHODS: Calretinin-Cre-ERT2-IKK2CA/tdTomato transgenic (TG) mice were generated and compared to littermate wild-type (WT) controls. At two months of age, the mice were treated for three days with tamoxifen causing continuous NFκB activation in enteric neuronal cells. One month later, the mice were treated with vehicle or 2.5% dextran sulfate sodium (DSS) for 7 days to induce colitis. Full thickness urinary bladder strips were stimulated with potassium and then EFS to induce nerve mediated contraction. The effect of atropine to inhibit muscarinic receptors and alpha, beta methylene ATP (ATP) to desensitize purinergic receptors was determined. RESULTS: Even though the bladder contractile response to high potassium stimulation was similar between sexes in both WT and TG mice, the EFS induced maximal contraction was greater in WT males than in WT females. Bladder strips from WT female mice had a significantly greater atropine resistant (purinergic) component of EFS induced contraction, compared to WT male mice, but this was not found in TG mice. The cholinergic component of EFS induced contraction was not different between male and female mice (WT or TG). Acute colitis significantly reduced KCl stimulated and nerve mediated contraction in bladder strips from WT female and male mice, and from TG female mice. Constitutive activation of neuronal NFκB preserved the nerve mediated and KCL induced contractile response in male mice. Acute colitis increased the purinergic component of nerve mediated contractions in male WT mice only. CONCLUSIONS: Experimentally induced colitis causes decreased bladder contraction. Neuronal NFκB signalling rescued the decreased bladder contraction due to colitis, perhaps through purinergic regulation in males. Neurogenic inflammation in the bladder may cause a larger degree of bladder dysfunction in female than in male mice perhaps because females have a greater purinergic component of nerve mediated bladder contraction that does not further increase due to colitis FUNDING SOURCE(S): RO1DK075684; P2ODK097819