Toll‐like Receptor 4 (TLR4) Knock‐out Mice Are Partially Protected from Diabetic Bladder Dysfunction

Abstract

Bladder dysfunction affects a majority of patients with diabetes and therapeutical options for diabetic bladder dysfunction (DBD) are limited. The innate immune system is now thought to be implicated in the pathogenesis of diabetic complications via inflammation and oxidative stress. We have previously shown that activation of Toll‐like receptor 4 (TLR4), a component of the innate immune system, was increased in the bladder of streptozotocin (STZ)‐induced diabetic mice, and that inhibition of TLR4 in vitro normalized the augmented bladder contraction observed in these mice. Here we hypothesized that deletion of TLR4 would ameliorate diabetic bladder dysfunction. We evaluated the development of DBD in TLR4 knock‐out (TLR4KO) and C57Bl/6 wild type (WT) mice treated with vehicle (CON) or STZ (50 mg/kg/day i.p. for 5 days). After 4 weeks of STZ treatment, we observed the same levels of glycemia in TLR4KO and WT mice (mg/dl: WT STZ=349±41, TLR4KO STZ=403±11). Bladder hypertrophy was slightly attenuated in TLR4KO compared to WT mice (% of CON bladder weight/body weight: WT STZ=145±8 TLR4KO STZ=126±11). Contraction to carbacholine (CCh) and electrical field stimulation (EFS) was increased in urothelium‐denuded bladder strips from WT STZ compared to WT CON mice, however no difference was observed between TLR4KO CON and TLR4KO STZ (CCh Emax in mN: WT CON=7.87±0.45, WT STZ=13.07±2.47, TLR4KO CON=8.01±1.35, TLR4KO STZ=9.23±3.13; mN contraction at 32 Hz EFS: WT CON=13.4±0.45, WT STZ=25.51±4.45, TLR4KO CON=14.67±1.66, TLR4KO STZ=19.07±6.45). We conclude that TLR4 contributes to the development of DBD independently of glycemia levels and the mechanism is coupled to innate immune activation in DBD. Support: NIDDK‐13GHSU302.