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Introduction: To evaluate the molecular pathways associated with bladder dysfunction in type 2 diabetes (T2D), we used a genetic mouse model with hepatocyte-specific double knockout of Insulin Receptor Substrates 1 & 2 (DKO) that develops T2D.
Materials & Methods: Bladders from different age DKO/floxed control mice were harvested and functional alterations were evaluated by muscle strip experiment ex vivo and cystometric experiment in vivo. Affymetrix mouse gene chip was employed to evaluate the expression of 45,000 genes in bladder. Cytokines in serum were determined using the Multiplex kit. Cultured Bladder Smooth Muscle Cell (BSMC) contraction in vitro was assayed by collagen gel retraction. The presence of macrophages, extent of apoptosis and expression of specific proteins were assessed with IHC and Western blot respectively.
Results: Young DKO mice exhibited hyperactive bladders (higher amplitudes of tension and frequency of contraction), while older mice demonstrated hypoactivity. Over 20 inflammatory genes were upregulated in the bladder of diabetic mice, most of which belonged to the TNF superfamily. Metabolic (ATPase, Rho GTPase, Rho kinase) and apoptotic-related (Caspase-3) genes were also upregulated. TNF-alpha was significantly upregulated in serum, and it stimulated the contraction of BSMC in culture. Systemic treatment with neutralizing TNFR1 in DKO mice corrected the diabetic cystopathy without affecting serum glucose.
Conclusion: The bladder of T2D mice transition from a hyperactive to a hypoactive state. Inflammatory/apoptotic mediators are upregulated in diabetic bladder dysfunction, and targeted systemic inhibition of TNFR improves bladder function without alteration of serum glucose.