Abstract
Atherosclerosis-associated pelvic ischemia has been reported to be a risk factor for bladder dysfunction and subsequent lower urinary tract symptoms (LUTS) in the elderly population. However, the molecular mechanisms of this association remain unclear. We hypothesized that stress-induced cellular responses might play a role in the pathogenesis of ischemia-induced bladder dysfunction. In the present study, the animal model of bladder ischemia was induced by bilateral partial arterial occlusion (BPAO) in rats. We found that BPAO significantly induced the presence of detrusor overactivity (DO) and upregulated the expression of several molecular reactions, including biomarkers in endoplasmic reticulum stress (78 kDa glucose-regulated protein, GRP78 and C/EBP-homologous protein, CHOP), autophagy (Beclin-1, p62 and LC3 II) and apoptosis (caspase 3). BPAO also disturbed the Kelch-like ECH-associated protein 1–nuclear factor erythroid-2-related factor 2 (Keap1–Nrf2) pathways. These responses might collectively alter muscarinic and purinergic signaling and contribute to the presence of DO in the ischemic bladder. Therapeutically, treatment with neither a muscarinic nor purinergic receptor antagonist restored bladder function. Interestingly, sulforaphane effectively attenuated ischemia-enhanced endoplasmic reticulum stress, autophagy and apoptosis in the bladder, subsequently ameliorated ischemia-induced bladder dysfunction and might emerge as a novel strategy to protect the bladder against ischemia-induced oxidative damage.
Highlights
Detrusor overactivity (DO) in men after transurethral resection of the prostate is associated with an increase in the vascular resistance of bladder vessels and a subsequent reduction of perfusion and hypoxia, suggesting that chronic ischemia may play a role in addition to bladder outlet obstruction[8]
In response to acute bilateral partial arterial occlusion (BPAO) (Fig. 2B-b), a significant redistribution of color-coded images of region of interest (ROI) 2 in the bladder body (Fig. 2B-b1) associated with a decline in high-flow areas and an increase in low-flow areas was observed (Fig. 2B-b3) when compared to the ROI 2 image (Fig. 2B-a1) and histogram (Fig. 2B-a3) before bladder ischemia indicating that the model of bladder ischemia was successfully induced following BPAO
The present study provided evidence of the involvement of endoplasmic reticulum (ER) stress, autophagy, and apoptosis in the bladder upon BPAO injury
Summary
Detrusor overactivity (DO) in men after transurethral resection of the prostate is associated with an increase in the vascular resistance of bladder vessels and a subsequent reduction of perfusion and hypoxia, suggesting that chronic ischemia may play a role in addition to bladder outlet obstruction[8]. Excess oxidative stress secondary to ischemia/ reperfusion has been reported to cause mitochondrial dysfunction and neurodegeneration, leading to bladder overactivity[13,14] Another cellular organelle, the endoplasmic reticulum (ER), may be involved in the cellular damage under conditions of oxidative stress[15]. We hypothesized that bladder ischemia that is induced in our experimental model might elicit oxidative stress and subsequent cellular responses, leading to bladder dysfunction. The attenuation of these stress-related alterations might alleviate damage and possibly provide insights into a novel strategy to protect against ischemia-induced bladder dysfunction
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