Diabetic bladder dysfunction (DBD) is a common urological complication of diabetes. Innate immune system activation via Toll-like receptor 4 (TLR4) leads to inflammation and oxidative stress and was implicated in diabetes pathophysiology. We hypothesized that bladder hypertrophy and hypercontractility in DBD is mediated by TLR4 activation. Wild type (WT) and TLR4 knock-out (TLR4KO) mice were made diabetic by streptozotocin (STZ) treatment and bladder contractile function and TLR4 pathway expression were evaluated. Immunohistochemistry confirmed expression of TLR4 in human and mouse bladder. Recombinant high mobility group box protein 1 (HMGB1) increased bladder TLR4 and MyD88 expression and enhanced contractile response to electrical field stimulation. Bladder expression of TLR4 and MyD88 and serum expression of HMGB1 were increased in STZ compared with control mice. Carbachol (CCh)-mediated contraction was increased in bladder from STZ mice and TLR4 inhibitor CLI-095 attenuated this increase. STZ diabetes induction in WT mice increased bladder weight and contractile responses to CCh and electrical field stimulation. TLR4KO mice were not protected from STZ-induced diabetes, however, despite similar levels of hyperglycemia as WT STZ mice, TLR4KO STZ mice were protected from diabetes-induced bladder hypertrophy and hypercontractility. These data suggest that TLR4 activation during diabetes mediates DBD-associated bladder hypertrophy and hypercontractility.
- Received April 15, 2016.
- Accepted September 14, 2016.
- © 2016 by the American Diabetes Association.