NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

Abstract

The NLRP3 inflammasome senses diabetic metabolites and initiates inflammation implicated in diabetic complications and neurodegeneration. No studies have investigated NLRP3 in diabetic bladder dysfunction (DBD), despite a high clinical prevalence. In vitro, we found that numerous diabetic metabolites activate NLRP3 in primary urothelial cells. In vivo, we demonstrate NLRP3 is activated in urothelia from a genetic type 1 diabetic mouse (Akita) by week 15. We then bred an NLRP3 2/2 genotype into these mice and found this blocked bladder inflammation and cystometric markers of DBD. Analysis of bladder innervation established an NLRP3-dependent decrease in overall nerve density and Ad-fibers in the bladder wall along with an increase in C-fiber populations in the urothelia, which potentially explains the decreased sense of bladder fullness reported by patients and overactivity detected early in DBD. Together, the results demonstrate the role of NLRP3 in the genesis of DBD and suggest specific NLRP3-mediated neuronal changes can produce specific DBD symptoms.

The Pharmacological Mechanism of Diabetes Mellitus-Associated Overactive Bladder and Its Treatment with Botulinum Toxin A

“…Recently, Hughes Jr. et al showed that the NLRP3 inflammasome, an intracellular sensor that detects endogenous danger signals and environmental irritants, can sense diabetic metabolites and induce inflammation implicated in diabetic complications and neurodegeneration [32]. Compared to NLRP3 genes of knocked out non-diabetic mice, NLRP3 genes of knocked out diabetic mice had a higher serum glucose level but similar voiding volume, voiding frequency, voiding efficiency, severity of bladder inflammation, bladder Aδ-fibers, and C-fibers density.…”

<p>Calcium Pyrophosphate And Monosodium Urate Activate The NLRP3 Inflammasome Within Bladder Urothelium Via Reactive Oxygen Species And TXNIP</p>

“…The cell isolation protocol was modified from a previously published method. 6,16 Briefly, rats were sacrificed and the bladders removed and placed in sterile PBS. Bladders were then inverted over an 18-gauge blunt tip needle, inflated with PBS, and a purse string suture was used to tie off the bladder.…”

“…In vitro experiments were performed essentially as previously described. 6 For agonist response studies, CPPD and MSU (InvivoGen, San Diego, CA) were prepared to the stock concentrations of 1.25 mg/mL and 12.5 µg/mL, respectively. Using PBS (for CPPD) or complete media (for MSU), 1:2 serial dilutions were prepared.…”

“…In fact, our own lab has highlighted the central importance of NLRP3 in triggering inflammation within bladder urothelium in different pathologic states. [6][7][8][9][10] The NLRP3 inflammasome is comprised, in part, of the nod-like receptor NLRP3, a structural co-factor protein called thioredoxininteracting protein (TXNIP), and the adaptor protein ASC. In the presence of activating stimuli, this complex forms, recruits, and activates caspase-1, resulting in the cleavage and maturation of the pro-inflammatory cytokines IL-1β and IL-18.…”

Coriolus versicolor alleviates diabetic cardiomyopathy by inhibiting cardiac fibrosis and NLRP3 inflammasome activation

“…The release of proinflammatory cytokines (IL‐1β, IL‐6, IL‐18, and TGF‐β1) is increased in DCM, and reducing inflammation is an effective strategy to impede DCM development (Li et al, ; Liu et al, ; Wen, Liang, Zhang, & Yang, ; Westermann et al, ). Recently, the nucleotide‐binding oligomerization domain‐like receptor (NLR) pyrin domain‐containing (NLRP) inflammasome has received increasing attention, which is a novel mediator in DM (Hughes et al, ; Wu et al, ). The NLRP3 inflammasome is composed of an NLRP3 receptor, an apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC) and precursor caspase‐1.…”