Mineralocorticoid receptor activation contributes to intestinal fibrosis through neutrophil gelatinase-associated lipocalin in preclinical models

Asma Amamou, Mathilde Leboutte, Jonathan Breton, David Ribet, Pierre-Alain Thiebaut, Christine Bôle-Feysot, Charlène Guérin, Kanhia Aublé, Elise Rebollo, Lise Ratel, Benjamin Bonnard, Alexis Goichon, Louison Leblond, Moutaz Aziz, Elodie Fermant, Frédéric Jaisser (), Guillaume Savoye and Rachel Marion-Letellier ()
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Asma Amamou: Inflammation and Microbiota-Gut-Brain Axis
Mathilde Leboutte: Inflammation and Microbiota-Gut-Brain Axis
Jonathan Breton: Inflammation and Microbiota-Gut-Brain Axis
David Ribet: Inflammation and Microbiota-Gut-Brain Axis
Pierre-Alain Thiebaut: Rouen University Hospital
Christine Bôle-Feysot: Inflammation and Microbiota-Gut-Brain Axis
Charlène Guérin: Inflammation and Microbiota-Gut-Brain Axis
Kanhia Aublé: Inflammation and Microbiota-Gut-Brain Axis
Elise Rebollo: Inflammation and Microbiota-Gut-Brain Axis
Lise Ratel: Inflammation and Microbiota-Gut-Brain Axis
Benjamin Bonnard: metabolic diseases and comorbidities
Alexis Goichon: Inflammation and Microbiota-Gut-Brain Axis
Louison Leblond: Rouen University Hospital
Moutaz Aziz: Rouen University Hospital
Elodie Fermant: Rouen University Hospital
Frédéric Jaisser: metabolic diseases and comorbidities
Guillaume Savoye: Inflammation and Microbiota-Gut-Brain Axis
Rachel Marion-Letellier: Inflammation and Microbiota-Gut-Brain Axis

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Intestinal fibrosis is a common complication in inflammatory bowel diseases with no specific therapy. Because mineralocorticoid receptor antagonism prevented inflammation and fibrosis in extra-intestinal organs, we aimed to evaluate mineralocorticoid receptor antagonism in intestinal fibrosis. Here we show that pharmacological or smooth cell specific deletion mineralocorticoid receptor antagonism prevented colon fibrosis development in male mice. In vitro, spironolactone prevented fibroblast proliferation and endothelial-to-mesenchymal transition. Neutrophil gelatinase-associated lipocalin silencing suppressed aldosterone-induced fibrosis markers and blunted colon fibrosis in mice. Chromatin immunoprecipitation showed mineralocorticoid receptor antagonist inhibits mineralocorticoid receptor binding on the neutrophil gelatinase-associated lipocalin promoter in activated smooth muscle cells. In conclusion, mineralocorticoid receptor antagonism or smooth muscle mineralocorticoid receptor deletion reduced colon fibrosis through the modulation of the neutrophil gelatinase-associated lipocalin pathway. Mineralocorticoid receptor may represent a novel therapeutic target in intestinal fibrosis and may allow the re-positioning in the field of inflammatory bowel diseases of drugs already marketed.

Date: 2025
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DOI: 10.1038/s41467-025-61401-0

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