# Role of Renin-Angiotensin-Aldosterone System during sarcoidosis granuloma formation

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2024 · $236,250

## Abstract

Sarcoidosis is a pulmonary and systemic granulomatous disease of unknown cause. To better understand
disease mechanisms, we have recently established a novel in vitro human granuloma model that shares many
structural and molecular features of the disease in human tissues, yielding novel insights into mechanisms
regulating early granuloma formation. In keeping with prior investigations and clinical experience linking
sarcoidosis to elevated leves of angiotensin converting enzyme (ACE) in sarcoidosis tissues, molecular
characterization of the sarcoidosis granuloma model indicates that macrophages participating in sarcoidosis
granuloma formation are regulated by the renin-angiotensin-aldosterone system (RAAS). Our strong
preliminary data shows that sarcoidosis macrophages produce aldosterone, a hormone that promotes
inflammation through the activation of mineralocorticoid receptors (MRs); and we further show that suppression
of the RAAS pathway (e.g., ACE inhibition) or inhibition of MRs attenuates granuloma formation. We
hypothesize that RAAS promotes pathological granuloma formation in patients with sarcoidosis through
activation of MRs. In the spirit of the R21 funding mechanisms, this project is highly innovative and has
important beneficial implications for advancing our understanding of sarcoidosis disease mechanisms and for
providing novel therapeutic targets and disease biomarkers. Aim 1 will determine if the balance between
ACE1 and ACE2 (a suppressor of ACE1-mediated inflammation) regulates sarcoidosis granuloma
formation by controlling angiotensin II levels and related angiotensin 1 receptor (ATR1) activation. We
posit that the balance between ACE and ACE2 influences the formation of granulomas in sarcoidosis patients.
Aim 2 will determine if aldosterone induced MR activation promotes NRF2/HO-1/STAT3 signaling to
promote sarcoidosis granuloma formation, featuring polarization towards CD163 macrophages. These
studies will determine if aldosterone promotes macrophage phagosome-activated signaling pathway
NRF2/HO-1/STAT3 to polarize macrophages towards a CD163 expressing phenotype that is predisposed to
aggregate and form granulomas. Aim 3 will be a pilot study designed to determine if aldosterone levels
achieved in the in vitro granuloma model are predictive of pulmonary sarcoidosis disease progression.
Currently, there are no reliable biomarkers predictive of sarcoidosis disease progression for prognostication
and to guide therapy, and aldosterone is a viable candidate. The short-term goals of this are to advancing
basic understanding of sarcoidosis disease mechanisms and to consider related therapeutic targets. Long-term
aspirations of this project are to address current deficiencies in the field of sarcoidosis as relates to
identifying novel disease-specific therapies (targeting granuloma formation), identifying novel biomarkers
predictive of disease progression, and to ultimately determine if it is feasible to repurpose widely available...

## Key facts

- **NIH application ID:** 10744243
- **Project number:** 5R21AI168804-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** ELLIOTT D CROUSER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $236,250
- **Award type:** 5
- **Project period:** 2022-11-18 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744243

## Citation

> US National Institutes of Health, RePORTER application 10744243, Role of Renin-Angiotensin-Aldosterone System during sarcoidosis granuloma formation (5R21AI168804-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10744243. Licensed CC0.

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