# Regulation of K+ balance by distal nephron TRPV4 channel

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $346,500

## Abstract

SUMMARY
 Tight regulation of K+ balance is fundamental for normal physiology. Disturbed K+ homeostasis is associated
with a wide spectrum of cardiovascular- and kidney-related pathologies. The distal nephron (DN), including the
connecting tubule (CNT) and the collecting duct (CD), is the major site of controlled potassium transport in the
kidney, which is essential to match urinary K+ excretion to varying dietary K+ intake. In this proposal, we posit
that the mechanosensitive Ca2+-permeable TRPV4 channel abundantly expressed in the DN is a critical
determinant of renal potassium handling capable of stimulating flow-dependent K+ secretion via maxi-K (BK)
channel and inhibiting H+-K+ ATPase-dependent K+ reabsorption. We generated abundant supportive evidence
that the TRPV4 activity in the DN is regulated by dietary potassium intake with its dysfunction causing significant
distortions of systemic K+ balance. TRPV4 -/- mice have a markedly reduced BK channel activity in the DN and
develop hyperkalemia when dietary potassium intake is high. On the contrary, TRPV4 deletion augments H+-K+
ATPase activity and protects against hypokalemia when dietary potassium intake is low. Overall, we hypothesize
that TRPV4 serves as a physiologically relevant kaliuretic factor during adaptations to dietary potassium regimen
by stimulating BK-mediated K+ secretion and inhibiting H+-K+ ATPase-dependent K+ reabsorption.
 To address this central hypothesis, we developed three specific aims: SA1: Examine molecular and
signaling determinants of TRPV4 regulation in the DN by dietary K+ intake. SA2: Establish the
importance of TRPV4 function for BK-mediated K+ secretion in the DN and define pathophysiological
ramifications of its disruption on systemic K+ balance. SA3: Explore the mechanism and relevance of
regulation of K+ reabsorption in the DN by TRPV4. To bring this project to fruition, we recruit strong
collaborative expertise and implement a comprehensive experimental arsenal which involves monitoring TRPV4
and BK channels activity with patch clamp electrophysiology, intracellular Ca2+ and H+-K+ ATPase-mediated pH
measurements, confocal immunofluorescent microscopy in native DN cells of rodents and humans, balance
studies upon manipulation of dietary K+ intake in conventional and genetically manipulated animals. Overall, we
expect to directly demonstrate the physiological relevance of mechanosensitive TRPV4 channel in the DN at the
systemic level and will define pathophysiological ramifications of TRPV4 dysfunction on systemic K+
homeostasis. Furthermore, this will urge development of novel strategies based on targeting TRPV4 to manage
life-threatening states of hyper- and hypokalemia in clinical setting.

## Key facts

- **NIH application ID:** 10439631
- **Project number:** 5R01DK119170-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Oleh Pochynyuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,500
- **Award type:** 5
- **Project period:** 2018-09-18 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439631

## Citation

> US National Institutes of Health, RePORTER application 10439631, Regulation of K+ balance by distal nephron TRPV4 channel (5R01DK119170-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439631. Licensed CC0.

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