# Interplay between Kir4.1/Kir5.1 channels, RAAS and electrolyte balance

> **NIH NIH F31** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $31,018

## Abstract

Abstract:
Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans afflicted with
hypertension, including approximately 75% of African American hypertensive patients. The effect of sodium on
blood pressure is dependent on diet composition, specifically on the Na+/K+ ratio. Diets supplemented with high
K+ are associated with a lower risk of major cardiovascular events. Despite highly relevant clinical and
translational evidence supporting the benefits of a high-potassium diet, there is a substantial lack in our
understanding of the underlying molecular mechanisms. Ion channels and transporters in the aldosterone-
sensitive distal nephron (ASDN) determine the transport rate and the subsequent urinary excretion of
electrolytes, including Na+ and K+. Inwardly rectifying K+ (Kir) channels, specifically Kir4.1/Kir5.1 (encoded by
Kcnj10 and Kcnj16 genes, respectively), are the major basolateral K+ channels in the ASDN and play an
important role in precisely maintaining electrolyte homeostasis in the kidney. Our previous studies revealed that
a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) results in decreased blood pressure, salt wasting
tubulopathy, and hypokalemia. Furthermore, when fed a high salt diet (HS; 4% NaCl), hypokalemia was
exacerbated and resulted in mortality of SSKcnj16-/- rats within a few days. Importantly, dietary potassium
supplementation as well as ENaC inhibition with benzamil treatment prevented salt-induced death. However,
specific mechanisms pertaining to the cardiorenal abnormalities in SSKcnj16-/- rats and the interaction of
Kir4.1/Kir5.1-mediated potassium transport with the renin-angiotensin-aldosterone system (RAAS, a major
hormone system that controls fluid and electrolyte balance in ASDN) remains unclear. In addition to SSKcnj16-/-
rats, we have created an SSKcnj10-/- model in which Kir4.1 (Kcnj10) has also been knocked out in the SS rat; these
two models enable us to assess the role of Kir4.1/Kir5.1 (Kcnj10/Kcnj16) channels in blood pressure control and
renal function. Given the reported associations of Kcnj10/Kcnj16 with a variety of cardiorenal diseases in
humans, 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 context of salt-
induced hypertension. Additionally, the capacity of Kir4.1/Kir5.1 channel activity to influence the RAAS, another
major controller of blood pressure, requires investigation. I hypothesize that the activity of Kir4.1/Kir5.1 channels
in the distal nephron is a major determinant of blood pressure through influencing the RAAS as well as electrolyte
balance by modulating ion channels and transporters in ASDN. There are two specific aims which will address
the proposed hypothesis: 1) To determine the influence of dysfunctional renal Kir4.1/Kir5.1 channels on ion
channels in the ASDN and on whole body electroly...

## Key facts

- **NIH application ID:** 10197121
- **Project number:** 5F31DK122647-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Anna D Manis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,018
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197121

## Citation

> US National Institutes of Health, RePORTER application 10197121, Interplay between Kir4.1/Kir5.1 channels, RAAS and electrolyte balance (5F31DK122647-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197121. Licensed CC0.

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