Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice

Abstract

Diabetic bladder dysfunction (DBD) is one of the most common complication of diabetes. Methylglyoxal (MGO), a highly reactive dicarbonyl compound formed as a by-product of glycolysis, is found at high levels in plasma of diabetic patients. Here, we explored the effects of chronic administration of MGO on micturition pattern (cystometry) and bladder contractility in vitro in healthy male C57/BL6 mice. Methylglyoxal was given at 0.5% in drinking water for 4 weeks. Exposure to MGO led to bladder tissue disorganization, edema of lamina propria, partial loss of urothelium and multiple leukocyte infiltrates. Filling cystometry revealed significant increases of micturition frequency and number of non-voiding contractions (NVCs) in the MGO group, clearly indicating an overactive bladder profile. Bladder contractions induced by electrical-field stimulation (EFS) and carbachol were significantly higher in the MGO group, while the muscarinic M 2 and M 3 mRNA expressions remained unchanged between groups. Additionally, MGO exposure induced upregulation of TRPA1 and down-regulation of TRPV1 and TRPV4 in bladder tissues. Methylglyoxal did not change the mRNA expression of the advanced glycation end products receptor (RAGE), but markedly increased its downstream NF-κB-iNOS signaling. The mRNA expression of cyclooxygenase-2 (COX-2) and reactive-oxygen species (ROS) levels remained unchanged. Altogether, our data show that 4-week MGO intake in mice produces an overactive bladder phenotype in addition to bladder inflammation and increased NF-kB/iNOS signaling. TRPA1 up-regulation and TRPV1/TRPV4 down-regulation may account for the MGO-induced bladder overactivity. Scavengers of MGO could be an option to ameliorate bladder dysfunction in diabetic conditions.

Enhanced RAGE Expression and Excess Reactive-Oxygen Species Production Mediates Rho Kinase-Dependent Detrusor Overactivity After Methylglyoxal Exposure

“…In animal models of diabetes, micturition dysfunction is characterized by increases in void number, volume, and capacity, despite conflicting data have been obtained depending on the model used ( Gasbarro et al, 2010 ; Leiria et al, 2011 ; Leiria et al, 2012 ; Wu et al, 2016 ; Ellenbroek et al, 2018 ; Yang et al, 2019 ; Kim et al, 2020 ). More recently, we have reported a model of bladder dysfunction induced by 4- and 12-weeks intake of MGO to healthy male mice ( de Oliveira et al, 2020 ; Oliveira et al, 2021 ), which differs from the classical diabetic animals in that MGO is not generated from the endogenous glucose metabolism and therefore does not affect the glucose levels and insulin sensitivity ( Medeiros et al, 2020 ). Urodynamic evaluation of MGO-treated mice revealed significant increases of micturition frequency and the number of non-voiding contractions (NVCs), along with enhanced in vitro bladder contractility to muscarinic and P2X1 receptor activation.…”

Improvement effect of gemigliptin on salivary gland dysfunction in exogenous methylglyoxal-injected rats

“…As previously reported, drinking water containing MGO resulted in about 12 % weight loss for mice when given in drinking water. The relative organ weight was slightly increased, but no significant change was observed in MGO compared with the control group [ 43 ].…”

A Spectrum of Age- and Gender-Dependent Lower Urinary Tract Phenotypes in Three Mouse Models of Type 2 Diabetes

“…Despite the abundant literature on these systemic processes, there are emerging signs of more local phenomena that target bladder tissues specifically. When methylglyoxal—a reactive by-product of glycolysis found at high levels in diabetic plasma—was administered to healthy mice for four weeks, an overactive bladder phenotype was observed in the complete absence of hyperglycemia [ 51 ]. Furthermore, an intriguing recent study from Chen et al [ 52 ] proposed a novel theory on the etiology of DVD.…”