Metformin abrogates the voiding dysfunction induced by prolonged methylglyoxal intake

Oliveira, Akila L.; Oliveira, Mariana Gonçalves de; Medeiros, Matheus da Silva; Mónica, Fabíola Z.; Antunes, Edson

doi:10.1016/j.ejphar.2021.174502

Cited by 8 publications

(23 citation statements)

References 53 publications

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“…Histological analysis of the bladders showed that MGO treatment caused small increases (despite significant) in bladder weight, urothelium thickness, detrusor thickness and collagen content. In bladders of male mice receiving MGO ( Oliveira et al, 2021 ), we detected a similar increase of the urothelium thickness, despite no alteration in the detrusor thickness was observed. With respect to the collagen content, the increases in bladder of males ( Oliveira et al, 2021 ) were markedly higher than the females (this study).…”

Section: Discussionsupporting

confidence: 54%

“…In bladders of male mice receiving MGO ( Oliveira et al, 2021 ), we detected a similar increase of the urothelium thickness, despite no alteration in the detrusor thickness was observed. With respect to the collagen content, the increases in bladder of males ( Oliveira et al, 2021 ) were markedly higher than the females (this study). We are uncertain about the reasons that explain the histological differences in bladders of male and females, but that may rely on the bioavailability of MGO and formation of AGEs, as well as on the ability of the glyoxalase system to detoxify MGO in each mouse sex.…”

Section: Discussionsupporting

confidence: 54%

“…In the present study, we administered 0.5% MGO for 12 weeks in female mice, after which MGO and F-AGEs were measured in serum. Similar to male mice ( Oliveira et al, 2021 ), higher levels of MGO and F-AGEs were found in MGO-exposed mice. No changes in glucose levels (this study) or insulin resistance ( Medeiros et al, 2020 ) were observed in the MGO-treated mice, confirming that elevated serum MGO was indeed generated by the oral intake of MGO rather than by the endogenous glucose metabolism, as observed in diabetes-associated diseases ( Yamagishi et al, 2012 ).…”

Section: Discussionmentioning

confidence: 62%

“…Digital images were obtained with a microscope Eclipse 80i (Nikon, Tokyo, Japan) equipped with a digital camera (DS-U3, Nikon). The thickness of urothelium and detrusor smooth muscle, and the collagen content were evaluated using the Fiji version of the ImageJ Software (Version 1.46r), according to a previous study ( Oliveira et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Erdogan

Liu

Arioglu‐Inan

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Dysfunction of the lower urinary tract (LUT) including urinary bladder and urethra (and prostate in men) is one of the most frequent complications of diabetes and can manifest as overactive bladder, underactive bladder, urinary incontinence, and as aggravated symptoms of benign prostate hyperplasia. We have performed a selective literature search to review existing evidence on efficacy of classic medications for the treatment of LUT dysfunction in diabetic patients and animals, i.e., α1-adrenoceptor and muscarinic receptor antagonists, β3-adrenoceptor agonists, and phosphodiesterase type 5 inhibitors. Generally, these agents appear to have comparable efficacy in patients and/or animals with and without diabetes. We also review effects of antidiabetic medications on LUT function. Such studies have largely been performed in animal models. In the streptozotocin-induced models of type 1 diabetes, insulin can prevent and reverse alterations of morphology, function, and gene expression patterns in bladder and prostate. Typical medications for the treatment of type 2 diabetes have been studied less often, and the reported findings are not yet sufficient to derive robust conclusions. Thereafter, we review animal studies with emerging medications perhaps targeting diabetes-associated LUT dysfunction. Data with myoinositol, daidzein, and with compounds that target oxidative stress, inflammation, Rac1, nerve growth factor, angiotensin II receptor, serotonin receptor, adenosine receptor, and soluble guanylyl cyclase are not conclusive yet, but some hold promise as potential treatments. Finally, we review nonpharmacological interventions in diabetic bladder dysfunction. These approaches are relatively new and give promising results in preclinical studies. In conclusion, the insulin data in rodent models of type 1 diabetes suggest that diabetes-associated LUT function can be mostly or partially reversed. However, we propose that considerable additional experimental and clinical studies are needed to target diabetes itself or pathophysiological changes induced by chronic hyperglycemia for the treatment of diabetic uropathy.

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Glyoxalase I is a novel target for the prevention of metabolic derangement

Miranda,

Haus

2023

Pharmacology & Therapeutics

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Metformin abrogates the voiding dysfunction induced by prolonged methylglyoxal intake

Cited by 8 publications

References 53 publications

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

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

Established and emerging treatments for diabetes-associated lower urinary tract dysfunction

Glyoxalase I is a novel target for the prevention of metabolic derangement

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