Early type 2 diabetic urothelium exhibits increased cellular senescence and an inhibitory effect on detrusor force
Authors: Klee Nicole S , Webb R Clinton 
Published: June 2021

IntroductionVarious forms of lower urinary tract dysfunction are important standalone medical conditions. Their prevalence increases with age and is a comorbidity to other health issues such as multiple sclerosis, Parkinson's disease, spinal cord injury, and diabetes. Up to 50% of all diabetic patients are affected with diabetic bladder dysfunction, which is characterized by a broad range of symptoms that can be categorized as either an overactive or underactive bladder. The total national costs for overactive bladder management alone are estimated to reach $82.6 billion in 2020, highlighting the need for more research into bladder dysfunction pathophysiology and novel therapeutics.Cellular senescence is an age‐related physiologic process in which cells undergo irreversible growth arrest induced by cellular stressors. While controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence is known to result in tissue dysfunction and has been implicated in multiple disease states, including diabetes.The objective of this study was to determine if increased cellular senescence contributes to symptoms of diabetic bladder dysfunction. We hypothesized that diabetic bladders would exhibit increased detrusor cellular senescence.MethodsType 2 diabetes was induced in male and female Wistar rats by utilizing a high fat diet, to induce insulin resistance and one low dose of streptozotocin (STZ; 30 mg/kg), to induce hyperglycemia and compromised pancreatic β‐cell function. Bladder tissue sections were stained with beta‐galactosidase (β‐gal), dihydroethidium (DHE), and hematoxylin‐eosin (H&E). Functional studies were performed in whole tissue and in urothelium denuded bladder strips in response to electrical field stimulation.ResultsThe HFD/STZ type 2 diabetic model resulted in increased fasting plasma glucose (237.5±39.48, 99.33±5.044; p=0.0159) and increased bladder wet weight (175.5±4.51, 102.2±2.37; p<0.0001) compared to control. Urinary bladder sections exhibited increased β‐gal and DHE staining within the urothelial layer indicating increased senescence and production of reactive oxygen species. Maximal force production in response to KCl (120mM) was significantly decreased in intact diabetic bladder strips (11.32±1.32) compared to both intact control (45±6.75; p=0.0016) and urothelium denuded diabetic strips (37.05±7.23; p=0.0074). Force in response to electrical field stimulation was decreased in intact diabetic bladder strips compared to intact control (p=0.0063) and urothelium denuded strips (p=0.001).ConclusionsIn the HFD/STZ model of type 2 diabetes, the urothelium exhibits increased cellular senescence and has an inhibitory effect on isometric force production. This suggests that diabetes induces changes within the urothelium, which alters bladder function. New therapies targeting the urothelium could be a novel approach to combat diabetic bladder dysfunction.Support or Funding InformationNIDDK Diabetic Complications Consortium, grant DK076169This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.