# Role of ANGII in mediating K secretion with a high K diet

> **NIH NIH R56** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $99,125

## Abstract

Project Summary
Angiotensin converting enzyme (ACE) inhibitors are regularly given to patients during early stages of chronic
kidney disease (CKD). However, the benefits of slowing the progression of CKD are often overshadowed by
dangerous episodes of hyperkalemia. In moderate CKD (stage 3; MCKD), the surviving nephrons adapt to high
K diets with an extremely enhanced rate of K secretion per nephron. These proposed studies are designed to
determine the importance of angiotensin II and why ACE inhibitors have such dangerous hyperkalemic effects
in renal failure beginning in stage 3. This information should provide alternative therapeutic choices designed to
prevent hypertension and hyperkalemia with high K consumption in moderate stages of renal failure. Aldosterone
responds to chronically elevated plasma [K] and enhances expression of the epithelial Na channel (ENaC) and
the Na-K-ATPase in the distal nephron. However, it is just as important to maintain a high rate of Na delivery to
ENaC and the Na-K-ATPase. It has been known for decades that a high K diet (HK) causes a large natriuretic
response. However, the signaling pathway is not understood. Based on our preliminary results and the literature,
we hypothesize that a high K diet stimulates urinary ANGII, which activates AT2 receptors, thereby
reducing Na reabsorption in the proximal tubule and increasing Na delivery to stimulate K secretion from
K channels in the distal nephron. Aim #1 will determine whether liver- or PT-generated ANGII enhances K
excretion in normal mice on HK and the 5/6 nephrectomized mouse model of renal failure. For this Aim, we will
employ liver only angiotensinogen knockout mice (LKO) and double liver plus PT angiotensinogen knockout
mice (DKO). Our preliminary results show that urinary ANGII is elevated by 5 to 8 fold in WT and LKO mice on
HK (5%) but is not elevated in DKO on HK. When placed on HK, DKO, but not WT or LKO, exhibit severe
hyperkalemia and a reduced urinary [K]/[creatinine]. We also find that PD123319, a blocker of ANGII 2 receptors
(AT2), reduce HKIN in WT mice. For Aim #2, we will determine whether the AT2 receptor-cGMP-kinase pathway
causes HKIN by inhibiting the Na-H exchanger 3 (NHE3) in the PT. Mice with a knock-out of the renal outer
medullary K channel (ROMK-KO) are a model of Bartters syndrome but also are absent ROMK-mediated K
secretion. ROMK-KO exhibit MCKD with GFR of approximately 55% of WT. Despite the compromised GFR and
lack of ROMK-mediated K secretion, ROMK-KO maintain K balance on HK. Our preliminary results indicate that
ROMK-KO compensate for the lack ROMK with enhanced HKIN that presumably stimulates large, Ca-activated
K channels (BK). The enhanced HKIN may result from our finding of increased renal guanylin expression in
ROMK-KO on HK. For Aim 3, we will explore whether enhanced guanylin-cGMP signaling of HK fed ROMK-KO
inhibits Na reabsorption in the PT and increases Na delivery to stimulate K secretion via BK.

## Key facts

- **NIH application ID:** 10248226
- **Project number:** 1R56DK126746-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** STEVEN SANSOM
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,125
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248226

## Citation

> US National Institutes of Health, RePORTER application 10248226, Role of ANGII in mediating K secretion with a high K diet (1R56DK126746-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10248226. Licensed CC0.

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