# Endothelial Cell Mineralocorticoid Receptor and Tubulointerstitial Fibrosis

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2020 · —

## Abstract

Project Summary/Abstract
Consumption of a western diet (WD) is a major contributor to the epidemic of obesity and associated insulin
resistance, hypertension and kidney disease that afflict our Veteran population. Chronic kidney disease is
increasing despite widespread use of renin-angiotensin-aldosterone system (RAAS) inhibition and
aggressive blood pressure control. Higher circulating aldosterone levels and excess mineralocorticoid
receptor (MR) activation, prevalent in obese, insulin resistant individuals, may be driving the increased risk for
progression of kidney disease, often in the face of adequate blood pressure control. Tubulointerstitial fibrosis
plays a major role in the development and progression of kidney disease. What little is known about MR
activation in tubulointerstitial fibrosis has been extrapolated from vascular studies where the development of
endothelial cell stiffness can be directly related to reductions in bioavailable nitric oxide (NO). Lowered NO
levels activate transglutaminase 2 (TG2) known to promote the extracellular matrix remodeling, synthesis of
fibrotic products and macrophage infiltration that lead to fibrosis. My pilot data indicate that consumption of a
WD promotes MR activation resulting in lower endothelial nitric oxide synthase (eNOS) activity, cell stiffness,
macrophage infiltration, a shift to an inflammatory M1/M2 polarization and vascular fibrosis. Preliminary data
link activation of the endothelial cell MR and TG2 activation but the role of endothelial MR activation and its
regulation of eNOS and TG2 in tubulointerstitial fibrosis remain to be determined.
In this context, the Objectives have been designed to investigate the mechanisms by which over-nutrition
promotes tubulointerstitial fibrosis through the endothelial aldosterone/MR system. We posit that the
endothelial MR regulates bioavailable NO and TG2, leading to stiffness and immune system activation. We will
use a high fat/sugar/salt diet (WD) known to activate the aldosterone/MR system and an endothelial-cell
specific MR knockout mouse (ECMR-/-) model to more specifically implicate the endothelial MR in
tubulointerstitial fibrosis. Fibrosis will be determined by light and electron microscopy, expression of fibrotic
markers and magnetization transfer MRI. To address Objective 1, I will measure endothelial cell stiffness
using atomic force microscopy, vascular reactivity using intravital microscopy, and resistance using ultrasound
imaging. To address Objective 2, I will focus on monocyte chemotaxis and Mφ polarization through FACS and
flow cytometry analysis of immune markers and M2 polarization along with other measures of inflammation,
such as cytokine expression. Objective 3 has been designed to investigate the importance of MR-, NO-, and
TG2-dependent actions on kidney fibrosis. I will employ a NO-donor and/or a TG2 inhibitor and measure
oxidative, inflammatory, extracellular cross-linking enzymes and fibrotic pathways to gauge molecular
...

## Key facts

- **NIH application ID:** 9898236
- **Project number:** 5I01BX003391-04
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Adam T Whaley Connell
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898236

## Citation

> US National Institutes of Health, RePORTER application 9898236, Endothelial Cell Mineralocorticoid Receptor and Tubulointerstitial Fibrosis (5I01BX003391-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898236. Licensed CC0.

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