Urothelial Senescence in the Pathophysiology of Diabetic Bladder Dysfunction-A Novel Hypothesis

Abstract

Diabetic bladder dysfunction (DBD) is a well-recognized and common symptom affecting up to 50% of all diabetic patients. DBD has a broad range of clinical presentations ranging from overactive to underactive bladder symptoms that develops in middle-aged to elderly patients with long standing and poorly controlled diabetes. Low efficacy of current therapeutics and lifestyle interventions combined with high national healthcare costs highlight the need for more research into bladder dysfunction pathophysiology and novel treatment options. Cellular senescence is an age-related physiologic process in which cells undergo irreversible growth arrest induced by replicative exhaustion and damaging insults. While controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence is known to result in tissue dysfunction through enhanced secretion of inflammatory factors. This review presents previous scientific findings and current hypotheses that characterize diabetic bladder dysfunction. Further, we propose the novel hypothesis that cellular senescence within the urothelial layer of the bladder contributes to the pro-inflammatory/pro-oxidant environment and symptoms of diabetic bladder dysfunction. Our results show increased cellular senescence in the urothelial layer of the bladder; however, whether this phenomenon is the cause or effect of DBD is unknown. The urothelial layer of the bladder is made up of transitional epithelia specialized to contract and expand with demand and plays an active role in transmission by modulating afferent activity. Transition from normal functioning urothelial cells to secretory senescence cells would not only disrupt the barrier function of this layer but may result in altered signaling and sensation of bladder fullness; dysfunction of this layer is known to result in symptoms of frequency and urgency. Future DBD therapeutics may benefit from targeting and preventing early transition of urothelial cells to senescent cells.

Keywords: diabetic bladder; diabetic cystopathy; lower urinary tract; senescence; urothelium.

Figure 1

Temporal progression of diabetic bladder dysfunction. Adapted from Daneshgari et al. (13).

Figure 2

Increased bladder weight in diabetic and aged animals. Bladder wet weight was measured in female and male control and diabetic animals (18–20 w of age; 1 month post-STZ injections) and in aged male animals (53 w of age). Diabetes was induced using the combination of a high fat diet and one streptozotocin injection (30 mg/kg) in Wistar animals.

Figure 3

Senescence associated-β-galactosidase staining is increased in aged Wistar urothelium compared to young control counterparts. Senescence associated-β-galactosidase staining (blue) and nuclear fast red counterstain in young (20 w of age) animals and old (53 w of age) animals (left and right panels, respectively). Representative images of bladder SA-β-galactosidase at 200X. SM, smooth muscle. UR, urothelium.

Figure 4

High glucose increases senescence associated-β-galactosidase staining in primary bladder smooth muscle cells. Senescence associated-β-galactosidase (blue) and nuclear fast red counterstain in high mannitol osmotic control (22 mM; left panel) and high glucose (22 mM; right panel) after a 4 day incubation. Representative images of primary bladder smooth muscle cell senescence associated-β-galactosidase at 100X.

Figure 5

Senescence associated-β-galactosidase staining is increased in diabetic urothelium compared to control counterparts. Senescence associated-β-galactosidase (blue) staining and nuclear fast red counterstain in control (Left) and diabetic (Right) bladders. Diabetes was induced using the combination of a high fat diet and one streptozotocin injection (30 mg/kg) in Wistar animals. Representative images of bladder senescence associated-β-galactosidase staining at 100X, inserts at 400X magnification. SM, smooth muscle. UR, urothelium.

Figure 6

Chronic hyperglycemia contributes to cellular stress and an accumulation of senescent cells. The presence of senescent cells further contributes to increased inflammation in the bladder wall, which leads to symptoms of diabetic bladder dysfunction.