The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic ob/ob mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.

Background/Objectives: Methylglyoxal (MGO) and subsequent activation of advanced glycation end products (AGEs)–RAGE receptor signaling has been implicated in the complications of diabetes mellitus (DM), such as bladder dysfunction. Chronic treatment with MGO leads to bladder overactivity, but the effects of acute MGO exposure have not yet been evaluated. Methods: In this study, we used female wild-type, endothelial nitric oxide (eNOS) knockout (eNOS^−/−), and triple (neuronal/endothelial/inducible) NOS^−/− mice to investigate the effects of incubation of MGO (10 to 300 µM) on bladder contractions induced by carbachol and electrical field stimulation (EFS). We also analyzed the activity of the MGO detoxification enzyme glyoxalase 1 (Glo1). Results: Incubation with MGO at 10 and 30 µM in urothelium-intact preparations produced marked detrusor hypercontractility to both carbachol and EFS that was abolished by urothelium removal. Detrusor hypercontractility was associated with the generation of reactive oxygen species (ROS), RAGE activation, Rho kinase sensitization, and activation of TRPA1 and TRPV4 channels. At higher concentrations (100 and 300 µM), MGO did not significantly affect the detrusor contractility to carbachol and EFS, but L-NAME pretreatment restored the hypercontractile state by MGO. Likewise, in bladder strips obtained from eNOS^−/− or triple NOS^−/− mice, MGO exposure (300 µM) significantly enhanced carbachol and EFS-induced contractions, indicating a major role for nitric oxide (NO) counteracting the hypercontractility. No concentration of MGO altered Glo1 activity in bladder tissues. Conclusions: In conclusion, progressive MGO accumulation may account for the transition from the initial hyperactive phase to the subsequent hypoactive decompensated phase of diabetic bladder dysfunction.