# Aldosterone Independent Activation of the Mineralocorticoid Receptor via IL-6 and Rac1 Induces Sodium Retention and Hypertension

> **NIH NIH K01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $163,080

## Abstract

Project Abstract
 The goal of this proposed project titled “Aldosterone Independent Activation of the Mineralocorticoid
Receptor via IL-6 and Rac1 Induces Sodium Retention and Hypertension” is to investigate the role of renal
dendritic cells (rDCs) in mediating cytokine-induced transactivation of the mineralocorticoid receptor (MR),
increasing sodium (Na+) reabsorption and blood pressure (BP). Excessive Na+ reabsorption is a main cause of
hypertension and end organ damage. The mechanisms mediating pathophysiological Na+ retention are
unknown; however, increased inflammation and excessive activation of distal nephron Na+ transporters, the
Na+ chloride cotransporter (NCC) and the epithelial Na+ channel (ENaC) play a role. However, the mechanisms
linking increased inflammation and cytokines to Na+ transporter activation are yet unidentified.
 Following a stressor, DCs cells secrete interleukin 6 (IL-6) producing a pro-inflammatory milieu. Our
preliminary data suggest that baseline blood pressure (BP) is regulated via rDCs, and the decreased systolic
BP levels observed in rDC-depleted mice may be due to decreased NCC protein expression. Further, our data
suggest that hypertension (HTN) increases serum IL-6 levels, while renal cortical IL-6 mRNA levels are
reduced in rDC-depleted mice. Our robust in vivo data suggest that intrarenal IL-6 infusion increases
phosphorylated (pT53) NCC, and total NCC, as well as ENaC expression. We also show that systemic IL-6,
plus high salt (HS, 4%) increases BP after 3 days. Together, these data strongly support a role for rDC-
mediating local IL-6 levels, and IL-6 increasing Na+ transporter expression and/or activity and BP.
 Moreover, our in vitro data demonstrates that IL-6 induces MR nuclear translocation and activation
of downstream mineralocorticoid response elements (MRE), via the small GTP-ase Rac1 and reactive oxygen
species (ROS) generation, and can directly activate thiazide-sensitive Na+ transport. Thus, we hypothesize that
intrarenal IL-6 transactivates the MR, increasing distal tubular Na+ reabsorption via NCC and ENaC leading to
hypertension. The studies in this proposal, when completed, will demonstrate that: 1) salt-sensitive HTN
activates rDCs, 2) rDCs contribute to increased intrarenal IL-6 levels during salt-sensitive HTN, 3) IL-6
independently transactivates the MR and 4) rDC-mediated IL-6 secretion increases NCC and ENaC Na+
transport leading to HTN.

## Key facts

- **NIH application ID:** 10260469
- **Project number:** 5K01DK115660-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Brandi Michele Wynne
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,080
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10260469

## Citation

> US National Institutes of Health, RePORTER application 10260469, Aldosterone Independent Activation of the Mineralocorticoid Receptor via IL-6 and Rac1 Induces Sodium Retention and Hypertension (5K01DK115660-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10260469. Licensed CC0.

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