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BACKGROUND:
Diabetic bladder dysfunction (DBD) in type 2 diabetes mellitus (DM2) affects up to 80% of individuals, but its underlying pathophysiology is poorly understood. Here we demonstrate a genetic mouse model with DM2 with hepatocyte-specific double knockout of Insulin receptor substrates 1 & 2 (DKO), which mimics the diabetic bladder dysfunction in humans.
METHODS:
Bladders from 6, 12, 16 and 20 week old DKO/control mice were harvested and functional alterations were evaluated in muscle strips ex vivo, by urodynamic and Voiding Stain on Paper test in vivo. The gene expression was evaluated by microarray. The level of TNF-α in serum was measured by ELISA. Cultured rat Bladder Smooth Muscle Cell (BSMC) contraction in vitro was assayed by collagen gel retraction. Protein expression was evaluated by Western blot and immunohistochemistry.

RESULTS:
Bladders of DKO animals exhibited detrusor overactivity at an early stage but hypo-activity at late stage. TNF superfamily genes were upregulated in bladder smooth muscle tissue. TNF-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α augmented the contraction of BSMC through upregulating Rho kinase activity and pMLC. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of RhoA signaling and reversed the bladder dysfunction without affecting hyperglycemia. TNFRI combined with the anti-diabetic agent, metformin, improved DBD beyond that achieved with metformin alone.
CONCLUSIONS:
Targeted inhibition of the TNF-α pathway may have a role in treating DBD and reducing the burden of the secondary complications of DM2.
Funding: AUA, NIH