Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

Hao, Yuan; Wang, Lu; Chen, Huan; Hill, Warren G.; Robson, Simon C.; Zeidel, Mark L.; Yu, Weiqun

doi:10.1172/jci.insight.122112

Cited by 18 publications

(40 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this work, we focused our attention on nucleotide signaling in the activation of contraction. The role of adenosine, which has been shown to inhibit human and mice bladder SMCs contractility [ 70 , 71 ] was not investigated in this work. Nevertheless, our work suggests the potential contribution of ecto-5′-nucleotidase in these effects.…”

Section: Discussionmentioning

confidence: 99%

NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

et al. 2021

View full text Add to dashboard Cite

Nucleotides released by smooth muscle cells (SMCs) and by innervating nerve terminals activate specific P2 receptors and modulate bladder contraction. We hypothesized that cell surface enzymes regulate SMC contraction in mice bladder by controlling the concentration of nucleotides. We showed by immunohistochemistry, enzymatic histochemistry, and biochemical activities that nucleoside triphosphate diphosphohydrolase-1 (NTPDase1) and ecto-5′-nucleotidase were the major ectonucleotidases expressed by SMCs in the bladder. RT-qPCR revealed that, among the nucleotide receptors, there was higher expression of P2X1, P2Y1, and P2Y6 receptors. Ex vivo, nucleotides induced a more potent contraction of bladder strips isolated from NTPDase1 deficient (Entpd1−/−) mice compared to wild type controls. The strongest responses were obtained with uridine 5′-triphosphate (UTP) and uridine 5′-diphosphate (UDP), suggesting the involvement of P2Y6 receptors, which was confirmed with P2ry6−/− bladder strips. Interestingly, this response was reduced in female bladders. Our results also suggest the participation of P2X1, P2Y2 and/or P2Y4, and P2Y12 in these contractions. A reduced response to the thromboxane analogue U46619 was also observed in wild type, Entpd1−/−, and P2ry6−/− female bladders showing another difference due to sex. In summary, NTPDase1 modulates the activation of nucleotide receptors in mouse bladder SMCs, and contractions induced by P2Y6 receptor activation were weaker in female bladders.

show abstract

Section: Discussionmentioning

confidence: 99%

NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Cystometrogram (CMG). CMG was performed with PBS infusion (25 μl/min) 64 . Mice were anesthetized by a subcutaneous injection of urethane (1.4 g/kg from 250 mg ml −1 solution in PBS) 30-60 min before surgery.…”

Section: Methodsmentioning

confidence: 99%

Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology

et al. 2020

Self Cite

View full text Add to dashboard Cite

The general anesthetic ketamine has been repurposed by physicians as an anti-depressant and by the public as a recreational drug. However, ketamine use can cause extensive pathological changes, including ketamine cystitis. The mechanisms of ketamine's antidepressant and adverse effects remain poorly understood. Here we present evidence that ketamine is an effective L-type Ca 2+ channel (Cav1.2) antagonist that directly inhibits calcium influx and smooth muscle contractility, leading to voiding dysfunction. Ketamine prevents Cav1.2-mediated induction of immediate early genes and transcription factors, and inactivation of Cav1.2 in smooth muscle mimics the ketamine cystitis phenotype. Our results demonstrate that ketamine inhibition of Cav1.2 signaling is an important pathway mediating ketamine cystitis. In contrast, Cav1.2 agonist Bay k8644 abrogates ketamine-induced smooth muscle dysfunction. Indeed, Cav1.2 activation by Bay k8644 decreases voiding frequency while increasing void volume, indicating Cav1.2 agonists might be effective drugs for treatment of bladder dysfunction.

show abstract

“…CMG was performed with PBS infusion (25 μL/min) as previously described. 32,33 Mice were anesthetized by a F I G U R E 1 AUR mouse model. A, Schematic diagram of AUR mouse model with the application of 50 or 80 cm water pressure.…”

Section: Cystometrogram (Cmg)mentioning

confidence: 99%

“…BSM strip EFS was carried out with a Grass S48 field stimulator (Grass Technologies, RI, USA) using standard protocols previously described. 32,33 EFS stimulation parameters were set as follows: voltage 50 V; duration: 0.05 ms; trains of stimuli: 3 s per single train; frequencies: 1, 2, 5, 10, 20, and 50 Hz.…”

Section: Electrical Field Stimulation (Efs)mentioning

confidence: 99%

Molecular mechanisms of voiding dysfunction in a novel mouse model of acute urinary retention

et al. 2021

Self Cite

View full text Add to dashboard Cite

Acute urinary retention (AUR) is a common urological emergency and affects a significant patient population. The inability to eliminate urine may lead to permanent damage to the bladder’s structure and functioning. However, we know little about the underlying molecular sequelae to the urine retention. To closely mirror the potential high pressures that patients with AUR could experience, we catheterized anesthetized female mice via the urethra and filled the bladder by pumping saline (25 µL/min) into the bladder lumen to 50 cm or 80 cm water pressure. A water column with designated height (50 or 80 cm) was then adjusted to maintain constant pressure in the bladder lumen for 30 minutes. Functional and morphological evaluations were performed from 0 to 24 hours after AUR treatment. Mice exhibited incontinence and overactivity with diminished voiding pressure. Significant injury was confirmed which revealed bladders with disrupted urothelial barrier, edematous lamina propria, and distorted muscle bundles. Bladder smooth muscle (BSM) from pressure‐treated mice have significantly diminished contraction force, suggesting that bladder voiding dysfunction can be attributed to impaired BSM contractility. Indeed, dysregulation of acetylcholine and purinergic signaling pathways were demonstrated, indicating that reduced efficacy of these pathways contributes to impaired BSM contractility. Finally, altered expression of β1‐integrin and extracellular matrix mediated mechanotransduction pathways were detected, suggesting a profound remodeling process. These data demonstrated an easy to perform, quantifiable, and reproducible AUR mouse model, which mimics well the characteristics of human AUR patients, and our data generate new insights into the molecular mechanisms that occur following AUR.

show abstract

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

Cited by 18 publications

References 58 publications

NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology

Molecular mechanisms of voiding dysfunction in a novel mouse model of acute urinary retention

Contact Info

Product

Resources

About