Evidence that methylglyoxal and receptor for advanced glycation end products (RAGE) are implicated in bladder dysfunction of obese diabetic ob/ob mice

Glycolytic overload in diabetes causes large accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO) and overproduction of advanced glycation end products (AGEs), which interact with its receptors (RAGE), leading to diabetes-associated macrovascular complications. Bladder is an organ that stays most in contact with dicarbonyl species, but little is known about the importance of MGO-AGEs-RAGE pathway to diabetes-associated bladder dysfunction. Here, we aimed to investigate the role of MGO-AGEs-RAGE pathway in bladder dysfunction of diabetic male and female ob/ob mice in comparison with wild type (WT) lean mice. Diabetic ob/ob mice were treated with the AGE-breaker alagebrium (ALT-711; 1 mg/kg) for eight weeks in drinking water. Compared with WT animals, male and female ob/ob mice showed marked hyperglycemia and insulin resistance, whereas fluid intake remained unaltered. Levels of total AGEs and MGO-derived hydroimidazolone 1 (MG-H1) and RAGE in bladder tissues, as well as fluorescent AGEs in serum were significantly elevated in ob/ob mice of either sex. Collagen content was also markedly elevated in bladders of ob/ob mice. Void spot assays in filter paper in conscious mice revealed significant increases of total void volume and volume per void in ob/ob mice with no alterations of spot number. Treatment with ALT-711 significantly reduced the levels of MGO, AGEs, RAGE, and collagen content in ob/ob mice. In addition, ALT-711 treatment normalized the volume per volume and increased the number of spots in ob/ob mice. Activation of AGEs-RAGE pathways by MGO in bladder wall may contribute to pathogenesis of diabetes-associated bladder dysfunction.