# Role of Detrusor Interstitial Cells in Overactive Bladder

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2022 · $435,037

## Abstract

SUMMARY
The bladder has the capability of maintaining low muscle excitability and low intravesical pressure throughout
most of the filling period. Loss of this ability to moderate muscle excitability is associated with development of
detrusor overactivity (DO). Detrusor smooth muscle cells (SMC) tend to be activated by stretch due to
expression of stretch-activated non-selective cation channels. So other cells, such as neurons or interstitial cells
appear to be necessary to restrain development of SMC excitability during filling. Recently, we discovered and
characterized a novel control mechanism that is intrinsic to detrusor muscles, provided by PDGFRα+ interstitial
cells and regulates detrusor excitability. PDGFRα+ cells have been identified and are abundant in human, guinea
pig and mouse detrusor muscles. The regulatory mechanism is composed of the following molecular and
functional elements: 1) PDGFRα+ cells express SK3 channels (Kcnn3) and high current density due to SK
channels. 2) SK channels in PDGFRα+ cells exert membrane potential-stabilizing effects on electrically coupled
SMC. 3) TRPV4 channels, also expressed by PDGFRα+ cells, provide a stretch-dependent source of Ca2+ that
activates SK channels during filling. In phase with loss of PDGFRα+ cells is the development of DO, as shown
by the development of excessive Ca2+ transients in SMC bundles and transient contractions during bladder filling.
From preliminary experiments, we have discovered that significant damage to PDGFRα+ cells occurs after spinal
cord injury (SCI) in an animal model that is known also to develop DO. We have also discovered a mechanism
for the damage to PDGFRα+ cells and a means of rescuing the cells after SCI. PDGFRα+ cells express
neurotrophin receptors (predominantly TrkB) and SCI are associated with reduced expression of TrkB. Reduced
TrkB signaling has been associated with apoptosis in neural and non-neural cells, and preliminary experiments
show that genes related to apoptotic signaling are enhanced in PDGFRα+ cells after SCI. We also found that
localized treatment of the detrusor with a TrkB agonist, shortly after SCI, rescued the PDGFRα+ cell phenotype
and prevented the development of DO. Therefore, in the current proposal we will pursue the following
overarching hypothesis: loss or defects in PDGFRα+ cells or in key molecular components responsible for the
inhibitory regulation provided by PDGFRα+ cells leads to detrusor dysfunction and development of detrusor
overactive phenotype. Completion of the specific aims of this study will provide exciting novel insights into how
the bladder is regulated during filling and how dysfunction might be managed after SCI by showing: i) PDGFRα+
cells are critical regulators of detrusor excitability during filling; ii) loss or damage to these cells leads to an DO
phenotype; iii) restoration of PDGFRα+ cells can rescue normal responses to bladder filling.

## Key facts

- **NIH application ID:** 10399607
- **Project number:** 5R01DK123237-03
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** SANG Don KOH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,037
- **Award type:** 5
- **Project period:** 2020-06-26 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399607

## Citation

> US National Institutes of Health, RePORTER application 10399607, Role of Detrusor Interstitial Cells in Overactive Bladder (5R01DK123237-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10399607. Licensed CC0.

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