The Gαi/o GPCR LPAR2 Acts as a Non-Classical Factor for Aldosterone Induced Injury in a Cardiomyocyte Model
- 1Brown University Division of Biology and Medicine
Abstract
Aldosterone is a key regulator of systemic sodium, potassium, and fluid homeostasis. Chronic elevation of aldosterone, as observed in primary aldosteronism, chronic heart and kidney diseases, promotes cardiac hypertrophy, inflammation, fibrosis, and heart failure, which are further enhanced in aging. Although these pathological effects are primarily attributed to the mineralocorticoid receptor (MR), emerging evidence suggests roles for nonclassical G protein-coupled receptor (GPCR) signaling. We identified lysophosphatidic acid receptor 2 (LPAR2) as a novel GPCR candidate that mediates aldosterone signaling in cardiomyocytes. Using AC16 human cardiomyocyte cells and reporter gene assays, we demonstrate that aldosterone activates a Gi/o-dependent GPCR pathway. Pharmacological inhibition of LPAR2 internalization confirms its specific reaction to aldosterone. Functional studies revealed that aldosterone-induced cardiomyocyte injury requires both MR and LPAR2, where specific antagonists to both receptors reduced the ability of aldosterone to induce collagen expression and cell death markers. These findings uncover a previously unrecognized non-classical mechanism of aldosterone action in the heart and highlight LPAR2 as a promising therapeutic target for aldosterone-driven cardiovascular disease.
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BibTeX
@misc{mohanty2026gαio,
title = {{The Gαi/o GPCR LPAR2 Acts as a Non-Classical Factor for Aldosterone Induced Injury in a Cardiomyocyte Model}},
author = {S. K. Mohanty and R. Gong and M. Tatar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755539},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755539v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The Gαi/o GPCR LPAR2 Acts as a Non-Classical Factor for Aldosterone Induced Injury in a Cardiomyocyte Model
AU - S. K. Mohanty
AU - R. Gong
AU - M. Tatar
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755539
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755539v1
AB - Aldosterone is a key regulator of systemic sodium, potassium, and fluid homeostasis. Chronic elevation of aldosterone, as observed in primary aldosteronism, chronic heart and kidney diseases, promotes cardiac hypertrophy, inflammation, fibrosis, and heart failure, which are further enhanced in aging. Although these pathological effects are primarily attributed to the mineralocorticoid receptor (MR), emerging evidence suggests roles for nonclassical G protein-coupled receptor (GPCR) signaling. We identified lysophosphatidic acid receptor 2 (LPAR2) as a novel GPCR candidate that mediates aldosterone signaling in cardiomyocytes. Using AC16 human cardiomyocyte cells and reporter gene assays, we demonstrate that aldosterone activates a Gi/o-dependent GPCR pathway. Pharmacological inhibition of LPAR2 internalization confirms its specific reaction to aldosterone. Functional studies revealed that aldosterone-induced cardiomyocyte injury requires both MR and LPAR2, where specific antagonists to both receptors reduced the ability of aldosterone to induce collagen expression and cell death markers. These findings uncover a previously unrecognized non-classical mechanism of aldosterone action in the heart and highlight LPAR2 as a promising therapeutic target for aldosterone-driven cardiovascular disease.
ER -