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

Abstract

Methylglyoxal (MGO) is a highly reactive dicarbonyl compound implicated in diabetes-associated diseases. In vascular tissues, MGO induces the formation of advanced glycation end products (AGEs) that bounds its receptor RAGE, initiating the downstream tissue injury. Outside the cardiovascular system, MGO intake produces mouse voiding dysfunction and bladder overactivity. We have sought that MGO-induced bladder overactivity is due to activation of AGE-RAGE-reactive-oxygen species (ROS) signaling cascade, leading to Rho kinase activation. Therefore, female mice received 0.5% MGO orally for 12 weeks, after which in vitro bladder contractions were evaluated in the presence or not of superoxide dismutase (PEG-SOD) or the Rho kinase inhibitor Y27632. Treatment with MGO significantly elevated the serum levels of MGO and fluorescent AGEs, as well as the RAGE immunostaining in the urothelium, detrusor, and vascular endothelium. RAGE mRNA expression in the bladder was also higher in the MGO group. Methylglyoxal significantly increased the ROS production in both urothelium and detrusor smooth muscle, with the increases in detrusor markedly higher than urothelium. The bladder activity of superoxide dismutase (SOD) was significantly reduced in the MGO group. Gene expressions of L-type Ca2+ channels, RhoA, ROCK-1, and ROCK-2 in bladder tissues were significantly elevated in the MGO group. Increased bladder contractions to electrical-field stimulation, carbachol α,β-methylene ATP, and extracellular Ca2+ were observed after MGO exposure, which was significantly reduced by prior incubation with either PEG-SOD or Y27632. Overall, our data indicate serum MGO accumulation elevates the AGEs levels and activates the RAGE-ROS signaling leading to Rho kinase-induced muscle sensitization, ultimately leading to detrusor overactivity.

Alu antisense RNA ameliorates methylglyoxal-induced human lens epithelial cell apoptosis by enhancing antioxidant defense

“…More experiments need to be performed in the future if we want to thoroughly prove the above hypothesis. DISCUSSION Previous works have proved that MGO can cause cell oxidative stress by scavenging SOD and glutathione [41][42][43] . The imbalance between ROS generation and antioxidant defense results in the ROS accumulation in cells, and accumulated ROS can damage cellular proteins, lipids, DNA and other biological molecules and cause cell apoptosis [33][34] .…”

Methylglyoxal and Advanced Glycation End Products (AGEs): Targets for the Prevention and Treatment of Diabetes-Associated Bladder Dysfunction?

“…Cystometric assays in male mice treated orally with MGO for an extended period (12 weeks) showed significant increases in the frequency of NVCs, bladder capacity, inter-micturition pressure, and residual volume [177]. In female mice treated with MGO for 12 weeks, cystometric assays confirmed urodynamic alterations such as increases in NVCs frequency, bladder capacity, inter-micturition pressure, and residual volume [15]. Using the model of spontaneous void spot assay (VSA) on filter paper, male mice treated with MGO for 12 weeks revealed an increased volume per void with no changes in the spot number as compared with the untreated group.…”

“…Interestingly, in mice treated orally with MGO for prolonged periods, voiding spot assays in conscious mice and urodynamic evaluation in anesthetized mice revealed significant increases in total void volume, volume per void, micturition frequency, and nonvoiding contractions number, along with enhanced in vitro bladder contractility [14]. In addition, elevated levels of MGO, AGEs, RAGE, and ROS were found in bladder tissues from mice chronically treated with MGO, pointing out that they could be important markers of DBD pathophysiology [15]. Similar data were obtained in bladder tissues of diabetic obese ob/ob mice [16].…”

Effector function and neutrophil cell death in the severity of sepsis with diabetes mellitus

“…Increased ROS, methylglyoxal (MGO) and AGEs increase signal transduction of cell death. Cell death pathways can be through death without inflammation (apoptosis, autophagy) and death with inflammation (necrosis, necroptosis, pyroptosis and suicide NET-osis) [44].…”