Abstract
BackgroundDiabetic bladder dysfunction (DBD) encompasses a broad spectrum of complications that affect over 50% of individuals with diabetes mellitus. While symptoms can greatly affect these individuals' quality of life, there are currently no targeted therapies available. Our focus is the early compensated phase, characterized by symptoms of urinary urgency and overactive bladder. Recent studies have shown that lysine acetylation, a post‐translational modification, may be associated with diabetic complications. We hypothesized that changes in acetyltransferase regulation result in increased lysine acetylation in bladder tissue, which in turn contribute to the pathogenesis of DBD.Materials and MethodsAdult male Wistar rats were randomized into two experimental groups. The diabetic group received a single intraperitoneal injection of 65 mg/kg of STZ in 0.01 M Sodium Citrate. Diabetes was confirmed with fasting glucose levels greater than 150 mg/dL. The control group received an equal volume of vehicle via intraperitoneal injection. 6 weeks post‐injection, DBD was confirmed with void spot assay. Rats were euthanized under isoflurane (via nasal in 100% O2) and the bladders were removed for molecular and histological analysis. Blood samples were collected for biochemical analysis.ResultsDiabetic animals showed higher levels of fasting glucose (433.5 ± 28.7 vs. 90.43 ± 1.36 mg/dL control, p<0.02, n=15), and decreased body weight (516.6 ± 18.8 vs. 376.1 ± 18.1 grams control, p<0.001, n=15). Diabetic animals also exhibited lipid profile changes, including increased triglycerides (522.7 ± 55.4 vs. 68.03 ± 11.7 mg/dL control, p<0.0002, n=10) and increased free fatty acids (0.663 ± 0.047 vs. 0.433 ± 0.034 mM control, p<0.005, n=13). Diabetic animals also showed increased bladder weight (0.2006 ± 0.0189 vs. 0.1344 ± 0.0557 grams control, p<0.015, n=8). Void spot assays confirmed an increase in overall voiding volume in diabetic rats (62.22 ± 12.2 vs. 6.198 ± 2.62 % of paper with urine control, p<0.01, n=10). Histological analysis showed detrusor hypertrophy in diabetic animals (1465.17 ± 62.92 vs. 1073.92 ± 125.84 μm control, p<0.0001). Global lysine acetylation was increased in experimental bladder tissue (55% in comparison to controls, p<0.005). A 90% decrease in HDAC7 expression was detected in diabetic rats compared to controls (p<0.0001, n=12).ConclusionOur findings suggest that downregulation of HDAC7 associated with hyperacetylation of diabetic bladder tissue indicates a potential therapeutic target for DBD. Using molecular and pharmacological approaches to overexpress HDAC7, we will confirm its role in DBD etiology. These molecular insights will improve our understanding of this complex condition, leading to the development of targeted interventions for the early phases of DBD.Support or Funding InformationIn‐house Grant NYITThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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