scholarly journals The Role of PIEZO1 in Urinary Bladder Function and Dysfunction in a Rodent Model of Cyclophosphamide-Induced Cystitis

2021 ◽  
Vol 2 ◽  
Author(s):  
Katharine I. K. Beča ◽  
Beatrice M. Girard ◽  
Thomas J. Heppner ◽  
Grant W. Hennig ◽  
Gerald M. Herrera ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Outlet Obstruction ◽  
Pain Syndrome ◽  
Mechanical Stretch ◽  
Bladder Pain Syndrome ◽  
Intravesical Instillation ◽  
Bladder Function ◽  
Bladder Pain ◽  
Vehicle Treatment ◽  
Female Wistar Rats

In the urinary bladder, mechanosensitive ion channels (MSCs) underlie the transduction of bladder stretch into sensory signals that are relayed to the PNS and CNS. PIEZO1 is a recently identified MSC that is Ca2+ permeable and is widely expressed throughout the lower urinary tract. Recent research indicates that PIEZO1 is activated by mechanical stretch or by pharmacological agonism via Yoda1. Aberrant activation of PIEZO1 has been suggested to play a role in clinical bladder pathologies like partial bladder outlet obstruction and interstitial cystitis/bladder pain syndrome (IC/BPS). In the present study, we show that intravesical instillation of Yoda1 in female Wistar rats leads to increased voiding frequency for up to 16 hours after administration compared to vehicle treatment. In a cyclophosphamide (CYP) model of cystitis, we found that the gene expression of several candidate MSCs (Trpv1, Trpv4, Piezo1, and Piezo2) were all upregulated in the urothelium and detrusor following chronic CYP-induced cystitis, but not acute CYP-induced cystitis. Functionally with this model, we show that Ca2+ activity is increased in urothelial cells following PIEZO1 activation via Yoda1 in acute and intermediate CYP treatment, but not in naïve (no CYP) nor chronic CYP treatment. Lastly, we show that activation of PIEZO1 may contribute to pathological bladder dysfunction through the downregulation of several tight junction genes in the urothelium including claudin-1, claudin-8, and zona occludens-1. Together, these data suggest that PIEZO1 activation plays a role in dysfunctional voiding behavior and may be a future, clinical target for the treatment of pathologies like IC/BPS.

scholarly journals Optogenetic silencing of primary afferents reduces evoked and ongoing bladder pain

2017 ◽  
Author(s):  
Vijay K. Samineni ◽  
Aaron D. Mickle ◽  
Jangyeol Yoon ◽  
Jose G. Grajales-Reyes ◽  
Melanie Pullen ◽  
...  
Keyword(s):  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Bladder Function ◽  
Optoelectronic System ◽  
Sensory Afferents ◽  
Bladder Pain ◽  
Before And After ◽  
Visceromotor Response ◽  
Cutaneous Hypersensitivity

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of bladder sensory afferents could be used to modulate bladder pain. Specifically, we chose to study the role of Nav1.8+ sensory afferents before and after induction of a mouse model of bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the Nav1.8+ promoter to selectively silence these neurons. Optically silencing Nav1.8+ afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of these fibers in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of Nav1.8+ fibers reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naïve mice. These results suggest that selective optogenetic silencing of bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain.

scholarly journals INTERSTITIAL CYSTITIS OR BLADDER PAIN SYNDROME: A MODERN VIEW OF A PROBLEM

2016 ◽  
Vol 1 (1) ◽  
pp. 65-69
Author(s):  
Баранова ◽  
Ekaterina Baranova ◽  
Кириленко ◽  
Elena Kirilenko ◽  
Онопко ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Interstitial Cystitis ◽  
Complex Disease ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Treatment Optimization ◽  
Bladder Pain ◽  
Literary Sources ◽  
Pathogenetic Therapy ◽  
Points Of View

The review of domestic and foreign literary sources for 2002–2014 made it possible to deepen into the problem of interstitial cystitis and put together different points of view and also to systematize the store of knowledge. Interstitial cystitis is a complex disease with marked clinical manifestation and defeat of urinary bladder with varying severity. For the purpose of diagnostics and treatment optimization of the disease in point in the review they presented the criteria whose existence will make it possible to make the diagnosis of interstitial cystitis. The multifactorial etiology of the disease requires the multiplane causal and pathogenetic therapy but more often empirical and symptomatic. In the article describe the algorithm of treatment of patients with the diagnosis of interstitial cystitis.

scholarly journals Expression and function of CCL2/CCR2 in rat micturition reflexes and somatic sensitivity with urinary bladder inflammation

2013 ◽  
Vol 305 (1) ◽  
pp. F111-F122 ◽  
Author(s):  
Lauren Arms ◽  
Beatrice M. Girard ◽  
Susan E. Malley ◽  
Margaret A. Vizzard
Keyword(s):  
Urinary Bladder ◽  
Therapeutic Potential ◽  
Pain Syndrome ◽  
Bladder Capacity ◽  
Bladder Pain Syndrome ◽  
Bladder Pain ◽  
Monocyte Chemoattractant Protein 1 ◽  
Functional Roles ◽  
Proinflammatory Mediators ◽  
Bladder Inflammation

Chemokines are proinflammatory mediators of the immune response, and there is growing evidence for chemokine/receptor signaling involvement in pronociception. Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder-related with at least one urinary symptom. We have explored the expression and functional roles of CCL2 (monocyte chemoattractant protein-1) and its high-affinity receptor, CCR2, in micturition reflex function and somatic sensitivity in rats with urinary bladder inflammation induced by cyclophosphamide (CYP) treatment of varying duration (4 h, 48 h, chronic). Real-time quantitative RT-PCR, ELISAs, and immunohistochemistry demonstrated significant ( P ≤ 0.01) increases in CCL2 and CCR2 expression in the urothelium and in Fast Blue-labeled bladder afferent neurons in lumbosacral dorsal root ganglia with CYP-induced cystitis. Intravesical infusion of RS504393 (5 μM), a specific CCR2 antagonist, reduced voiding frequency and increased bladder capacity and void volume in rats with CYP-induced cystitis (4 h), as determined with open outlet, conscious cystometry. In addition, CCR2 blockade, at the level of the urinary bladder, reduced referred somatic sensitivity of the hindpaw and pelvic region in rats with CYP treatment, as determined with von Frey filament testing. We provide evidence of functional roles for CCL2/CCR2 signaling at the level of the urinary bladder in reducing voiding frequency and somatic sensitivity following CYP-induced cystitis (4 h). These studies suggest that chemokines/receptors may be novel targets with therapeutic potential in the context of urinary bladder inflammation.

scholarly journals Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

2011 ◽  
Vol 301 (2) ◽  
pp. F252-F262 ◽  
Author(s):  
Lauren Arms ◽  
Margaret A. Vizzard
Keyword(s):  
Urinary Bladder ◽  
Bladder Capacity ◽  
Intravesical Instillation ◽  
Bladder Function ◽  
Rat Urinary Bladder ◽  
Akt Phosphorylation ◽  
Somatic Pain ◽  
Time Points ◽  
Bladder Inflammation ◽  
Female Wistar Rats

AKT phosphorylation following peripheral nerve injury or inflammation may play a role in somatic pain processes and visceral inflammation. To examine such a role in micturition reflexes with bladder inflammation, we induced bladder inflammation in adult female Wistar rats (200–300 g) by injecting cyclophosphamide (CYP) intraperitoneally at acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every third day for 10 days) time points. Western blot analyses of whole urinary bladders showed significant increases ( P ≤ 0.01) in phosphorylated (p) AKT at all time points; however, the magnitude of AKT phosphorylation varied with duration of CYP treatment. Immunohistochemical analyses of pAKT immunoreactivity (pAKT-IR) in cryostat bladder sections demonstrated duration-dependent, significant ( P ≤ 0.01) increases in pAKT-IR in both the urothelium and detrusor smooth muscle of CYP-inflamed bladders. Additionally, a suburothelial population of pAKT-IR macrophages (CD68-, MAC2-, and F4/80-positive) was present in chronic CYP-treated bladders. The functional role of pAKT in micturition was evaluated using open, conscious cystometry with continuous instillation of saline in conjunction with administration of an inhibitor of AKT phosphorylation, deguelin (1.0 μg/10 μl), or vehicle (1% DMSO in saline) in control (no inflammation) and CYP (48 h)-treated rats. Bladder capacity, void volume, and intercontraction void interval increased significantly ( P ≤ 0.05) following intravesical instillation of deguelin in CYP (48 h)-treated rats. These results demonstrate increased AKT phosphorylation in the urinary bladder with urinary bladder inflammation and that blockade of AKT phosphorylation in the urothelium improves overall bladder function.

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