# Role of PIEZO Channels in Bladder Function and Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $593,666

## Abstract

Abstract: During filling and voiding, the degree of tension in the bladder wall must be sensed and then
relayed to the central nervous system, otherwise bladder dysfunction ensues. While there is a general
understanding of the role of sensory neurons (i.e., wall mechanoceptors) in these events, we have fewer
insights into how non-neuronal tissues contribute to tension sensation and transduction in the bladder. Our
studies focus on the urothelium, which forms the direct interface between the bladder wall and the urinary
space. This tissue responds to changes in tension by modulating its ion transport, membrane traffic, and
release of mediators, which are hypothesized to alter bladder function, in part via a local urothelial:afferent
reflex. However, we still have limited insights into how tension in the plasma membrane of urothelial cells is
sensed, what is the nature of the downstream pathways that are activated in response to stretch, or how do
these events contribute to bladder function and dysfunction. We hypothesize that urothelial-expressed PIEZO
channels act as mechanosensors that in response to bladder filling promote Ca2+ entry, mediator release, and
signaling to afferent nerve processes, promoting normal bladder function. We further hypothesize that
dysregulation of PIEZO-dependent mechanotransduction in the urothelium will lead to bladder dysfunction. In
Specific Aim 1, we will determine if PIEZO channels act as bona fide mechanosensors by demonstrating the
following: (i) that functional PIEZO channels are expressed at the surface of urothelial cells; (ii) that urothelial
expressed PIEZO channels respond to physiologically relevant stimuli (i.e., bladder filling); (iii) that PIEZO
channels are required for mechanically regulated events including membrane traffic and mediator release; (iv)
and that expression of loss-of-function or gain-of-function PIEZO mutants will lead to altered urothelial
responses. In Specific Aim 2, we seek to understand how PIEZO channels promote urothelial:afferent
signaling. Using novel tools, including ex vivo bladder imaging, we will explore the mechanisms by which
PIEZO channels stimulate increases in intracellular Ca2+ ([Ca2+]i). Because PIEZO channels rapidly inactivate,
there is likely to be a mechanism to amplify the original signal. Thus, we will define whether Ca2+-induced Ca2+
release or membrane depolarization act downstream of PIEZO channels to increase [Ca2+]i. We will also
determine if the PIEZO-triggered rise in [Ca2+]i is critical for stimulating exocytosis and mediator release in the
urothelium, and if urothelial PIEZO channels modulate urothelial:afferent signaling. In Specific Aim 3, we will
begin to explore whether urothelial PIEZO channels contribute to bladder function and/or dysfunction.
Specifically, we will determine whether loss of PIEZO expression or function results in bladder underactivity
and if PIEZO channels with gain-of-function mutations lead to bladder overactivity. Finally, w...

## Key facts

- **NIH application ID:** 9986751
- **Project number:** 5R01DK119183-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gerard L Apodaca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $593,666
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986751

## Citation

> US National Institutes of Health, RePORTER application 9986751, Role of PIEZO Channels in Bladder Function and Dysfunction (5R01DK119183-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986751. Licensed CC0.

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