# Role of basolateral K channels in renal salt handling and BP control

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $356,313

## Abstract

Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans affected by
hypertension, including approximately 75% of African American hypertensive patients. Basolateral inwardly
rectifying K+ (Kir) channels, specifically Kir4.1 and Kir4.1/Kir5.1 (encoded by Kcnj10 and Kcnj16 genes), play a
dominant role in modulating water and electrolyte transport in the aldosterone-sensitive distal nephron. Renal
Kir4.1/Kir5.1 heterotetramer is a primary basolateral channel at the distal and collecting ducts principal cells and
plays an essential role in the regulation of plasma K+ level and Na+ reabsorption. The malfunction of this channel
caused by genetic or medication-related factors can be directly involved in hypokalemic, hyperkalemic and
hypertensive pathologies in humans. From the other side, precise pharmacological or genetic modulation of
Kir4.1or Kir5.1 subunits may provide a new useful tool to the control of electrolyte balance in the body and will
open new ways to treat and prevent the development of salt-sensitive hypertension and kidney damage. The
Dahl Salt-Sensitive (SS) rat, a naturally occurring model of salt-sensitive hypertension, recapitulates many
aspects of progressive human disease providing key insights into mechanisms underlying salt-sensitivity. We
have created two rat models in which Kir4.1or Kir5.1 have been knocked out in the SS rat (SSKcnj10-/- and SSKcnj16-
/- rats, respectively), enabling us to assess the role of both Kir4.1and Kir4.1/Kir5.1 channels in the control of K+
homeostasis and the development of salt-sensitive hypertension. Given the reported associations of Kir4.1/Kir5.1
with a variety of cardiorenal diseases, it is important to understand the mechanisms by which Kir4.1/Kir5.1 can
influence electrolyte homeostasis, the activity of other channels and transporters, and blood pressure control in
the setting of salt-induced hypertension. The Specific Aims of this proposal are 1) To define the dynamic interplay
between Kir4.1/Kir5.1, NCC, ENaC channels/transporters and RAAS in the kidney and the role of these
mechanisms in the control of electrolyte balance in the body. Changes in RAAS hormones under high salt and
dietary potassium supplements, basolateral membrane potential in individual cells of DCT and CCD tubules,
NCC and ENaC activity, sodium/potassium homeostasis, and the effect of a mineralocorticoid receptor inhibitors
will be tested in SSKcnj10-/- and SSKcnj16-/- rats. 2) To determine if pharmacological inhibition of Kir4.1/Kir5.1
attenuates salt-induced hypertension. Our preliminary and published experiments revealed that nortriptyline, an
FDA-approved second-generation tricyclic antidepressant, significantly decreases Kir4.1/Kir5.1-mediated K+-
selective conductance and modulates ENaC activity in CCD cells. Using novel specific compounds, such as
VU992, VU690, and VU726 in WT and SSKcnj16-/- rats, we will determine the viability of Kir4.1/Kir5.1 as a
pharmacological target to re...

## Key facts

- **NIH application ID:** 10747985
- **Project number:** 5R01DK126720-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Oleg Palygin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $356,313
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747985

## Citation

> US National Institutes of Health, RePORTER application 10747985, Role of basolateral K channels in renal salt handling and BP control (5R01DK126720-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10747985. Licensed CC0.

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