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 M2 and M3 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.
Highlights
Diabetes mellitus is a chronic progressive metabolic disorder with multiple serious complications (American Diabetes Association (ADA), 2018)
The findings described above highlight the role of MGO in several complications of diabetes; little is known about its effects on the bladder
The direct activation of muscarinic receptors by carbachol produced significantly higher contractions in bladders from MGO compared with control group with no concomitant changes in muscarinic M2 and M3 receptor mRNA expressions, which may suggest that the resulting increase in bladder contractions reflect the muscarinic downstream involving higher intracellular calcium via inositol
Summary
Diabetes mellitus is a chronic progressive metabolic disorder with multiple serious complications (American Diabetes Association (ADA), 2018). Diabetic bladder dysfunction (DBD) is one of the most common complications of diabetes, affecting up to 50% of the patients (Gomez et al, 2011). Methylglyoxal Induces Bladder Overactivity in 2030 (Shaw et al, 2010), a large proportion of them is expected to be afflicted by DBD, which not a lifethreatening condition, it greatly impairs the individual’s quality of life. DBD was recognized as a progressive group of bladder symptoms, characterized in the early stages by bladder overactivity and increased urinary frequency, while in the later stages, after prolonged hyperglycemia and insulin resistance, by an insensible and decompensated bladder, resulting in impaired bladder emptying and high residual volumes (Yuan et al, 2015; Daneshgari et al, 2017). Despite the advances in understanding DBD, the mechanisms underlying bladder dysfunction in diabetic patients are incompletely understood
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