# Regulation of K and H secretion by intercalated cells

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $202,907

## Abstract

Intercalated cells (ICs) secrete H+/HCO3- into the aldosterone-sensitive distal nephron (ASDN). Emerging
evidence has identified nontraditional roles for ICs including absorption of filtered Na+ and Cl-, flow-induced K+
secretion (FIKS) and participation in innate immunity. Apical BK channels in ICs are activated by a flow-
stimulated increase in intracellular Ca2+ concentration ([Ca2+]i). The rapid initial mechanoinduced increase in
[Ca2+]i reflects basolateral Ca2+ entry and release of internal Ca2+ stores. Piezo1, a member of a family of
mechanosensitive non-selective cation channels, is expressed along the basolateral membrane of ICs and
principal cells (PCs) in the ASDN. In preliminary studies, we found that a Piezo1 inhibitor dampens the flow-
induced [Ca2+]i response in cortical collecting ducts (CCDs), whereas an activator increases [Ca2+]i in CCDs
perfused at slow flow rates. These observations suggest that Piezo1 mediates flow-induced early basolateral
Ca2+ entry. Mucin 1 (or Muc1) is an apical surface glycoprotein expressed in distal aspects of the nephron, and
is most robust in type A (H+-secreting) ICs and in type B (HCO3--secreting) ICs. The physiologic role of Muc1 in
ICs is uncertain. In preliminary studies, we found that the cytoplasmic (V1) and transmembrane (V0) domains of
V-ATPase dissociate in ICs of Muc1 knockout (KO) mice. Muc1 KO animals have impaired urinary acidification
following an acid load. These data suggest that Muc1 regulates V-ATPase V1/V0 domain assembly in ICs. Based
on these observations, we hypothesize that (i) Piezo channels function as mechanosensors in the ASDN and
enable FIKS by facilitating basolateral Ca2+ entry in ICs, and (ii) Muc1 modulates specific signaling pathways
that regulate the assembly of V1/V0 domains and functional V-ATPase in specific H+-secreting epithelia,
including ICs. Experiments proposed in Aim 1 will define the role of mechano-activated Piezo1 channels in the
cellular response to an increase in tubular flow and to dietary K+ adaptation. The functional impact of
pharmacologic (activators and inhibitors) and genetic (KO) manipulations of Piezo1 will be assessed at the level
of single tubules ([Ca2+]i, JK and JNa) and animals (clearance studies) subjected to variable dietary K+. In Aim
2, we will define the role of Muc1 in the regulated assembly and functional expression of the V-ATPase in H+-
secreting epithelia. We will determine whether Muc1 is required for the assembly of V1/V0 domains of the V-
ATPase in H+-secreting ICs and determine the functional consequences of a lack of assembly of V-ATPase
V1/V0 domains in H+-secreting ICs. Muc1-dependent signaling pathways that regulate V1/V0 domain assembly
and V-ATPase functional activity in H+-secreting ICs will be defined. We expect that the results of our proposed
studies will uncover novel and unexpected pathways involved in urinary K+ and H+ excretion and identify potential
targets for novel therapies to treat K+ and acid-base imbal...

## Key facts

- **NIH application ID:** 10119977
- **Project number:** 2R01DK038470-31A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Rebecca P Hughey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,907
- **Award type:** 2
- **Project period:** 1986-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119977

## Citation

> US National Institutes of Health, RePORTER application 10119977, Regulation of K and H secretion by intercalated cells (2R01DK038470-31A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119977. Licensed CC0.

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