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

Abstract

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.

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

“…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]. The antihyperglycemic drug metformin [17][18][19] and polyphenols like resveratrol and epigallocatechin-3-gallate [20] can directly scavenge MGO, explaining, at least in part, their capacity to ameliorate diabetes-associated bladder dysfunction.…”

“…Likewise, in high-fat fed mice, levels of plasma and urine levels of MGO were significantly higher than animals kept on low-fat diet [179]. Diabetic obese ob/ob mice also displayed elevated serum MGO compared with normoglycemic animals [16] (Table 1). Bladders from male mice treated orally with MGO for 4 weeks revealed tissue disorganization, partial loss of the urothelium, and mucosal edema along with marked cell infiltration [14].…”

“…Similarly, in the STZ-or diet-induced obesity models, ob/ob male mice exhibit bladder dysfunction characterized by increases in urine volume and in vitro bladder smooth muscle contractions [119]. Increases in total void volume and volume per void with no alterations of spot number were observed in fiveweek-old male and female ob/ob mice, as evaluated by void spot assays [16]. Four-and six-month-old ob/ob mice exhibited some degree of bladder dysfunction such as increases in total urine volume and number of primary void spots, although that depended on animal sex and animal age [115].…”

“…Likewise, hyperglycemic diabetic leptin-deficient male and female mice (ob/ob) exhibit bladder dysfunction, as evidenced by the increases in total void volume and volume per void (void spot assay) in addition to high collagen content in the bladders [16]. These bladder alterations were associated with high levels of total AGEs, MG-H1 and RAGE found in bladder tissues, which is consistent with the findings that the AGE breaker alagebrium (ALT-711) at 1 mg/kg during 8 weeks in the drinking water nearly reversed all the molecular and functional alterations in ob/ob mice [16] (Table 3). Table 3.…”

“…Table 3. Protective effects of alagebrium (ALT-711) on the levels of total AGEs, MG-H1, RAGE and collagen in bladder tissues of obese diabetic ob/ob mice [16].…”