| Authors |
Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K,
Sullivan MP, Adam RM, White MF, Olumi AF
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| Submitted By |
Aria Olumi on 3/12/2014 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2012 |
| Date Published |
8/1/2012 |
| Volume : Pages |
61 : 2134 - 2145 |
| PubMed Reference |
22688336 |
| Abstract |
Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic
patients. However, the molecular mechanisms underlying DBD remain elusive
because of a lack of appropriate animal models. We demonstrate DBD in a mouse
model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions
(double knockout [DKO]), which develops type 2 diabetes. Bladders of DKO animals
exhibited detrusor overactivity at an early stage: increased frequency of
nonvoiding contractions during bladder filling, decreased voided volume, and
dispersed urine spot patterns. In contrast, older animals with diabetes
exhibited detrusor hypoactivity, findings consistent with clinical features of
diabetes in humans. The tumor necrosis factor (TNF) superfamily genes were
upregulated in DKO bladders. In particular, TNF-a was upregulated in serum and
in bladder smooth muscle tissue. TNF-a augmented the contraction of primary
cultured bladder smooth muscle cells through upregulating Rho kinase activity
and phosphorylating myosin light chain. Systemic treatment of DKO animals with
soluble TNF receptor 1 (TNFRI) prevented upregulation of Rho A signaling and
reversed the bladder dysfunction, without affecting hyperglycemia. TNFRI
combined with the antidiabetic agent, metformin, improved DBD beyond that
achieved with metformin alone, suggesting that therapies targeting TNF-a may
have utility in reversing the secondary urologic complications of type 2
diabetes.
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