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

Katharine I K Beča,Mark T Nelson,Gerald M Herrera,Beatrice M Girard,Thomas J Heppner,Margaret A Vizzard,Grant W Hennig

doi:10.3389/fpain.2021.748385

Katharine I K Beča, Mark T Nelson + Show 5 more

Open Access

https://doi.org/10.3389/fpain.2021.748385

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Abstract

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.

Highlights

Proper micturition requires the urinary bladder to act as a reservoir for storage, and a pump for the elimination of urine
Previous studies in unconscious rats have shown that blockade of PIEZO1 using the non-selective mechanosensitive ion channels (MSCs) antagonist, GsMTx4 (2.5 μM), increases the intermicturition interval when infused directly into the bladders of naïve rats, and rats chronically treated with CYP [17]
We hypothesized that activating PIEZO1 via intravesical infusion of Yoda1 directly into the bladder would recapitulate the hallmark symptom of increased voiding frequency commonly seen in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) and animal models using CYP-treatment

Summary

Introduction

Proper micturition requires the urinary bladder to act as a reservoir for storage, and a pump for the elimination of urine. PIEZO1 in Rodent Bladder Function stretch-induced activation, these channels open a non-selective cationic pore to allow the influx of ions, including calcium (Ca2+), into the urothelial cell [3,4,5] This influx of Ca2+ leads to a release of several neuromodulators, including ATP, which bind to receptors on afferent nerve terminals in the deeper layers of the bladder wall. Evidence of this comes from studies that show the addition of TRPV1 and TRPV4 agonists onto urothelial cells increases ATP release from these cells, while the addition of antagonists decreases ATP release [1, 5,6,7] This decrease in ATP release following antagonist application is mirrored by impaired stretch evoked responses in bladders from Trpv1−/− and Trpv4−/− mice along with low-amplitude bladder activity resulting in increased bladder capacity [1, 2]. Though this mechanism of mechanotransduction is well-established in TRP channels, over the last decade, a novel MSC was identified in the urinary bladder called PIEZO1

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