P0091 Role of smooth muscle cells-overexpressed mineralocorticoid receptor in intestinal fibrosis: gut characterization of new murine lineage.

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Abstract Background Intestinal fibrosis is a key therapeutic challenge in the management of inflammatory bowel diseases (IBD) due to the lack of anti-fibrotic therapies. Recently, we reported that genetic deletion of mineralocorticoid receptor (MR) in smooth muscle cells (SMCs) alleviated intestinal fibrosis in a preclinical model, through modulation of neutrophil gelatinase-associated lipocalin (NGAL) expression1. Now, we aim to investigate the cellular and molecular mechanisms driven by MR overactivation in SMCs in intestinal fibrosis. Methods Tamoxifen injection in male and female SMA-CreERT2 x pCAG-STOP Neo-FLOX-mMR mice induced Cre activity to overexpress murine MR in SMCs (SMA MORE). Wild-type (WT) mice did not express SMA-CreERT2 and therefore had native expression of MR (Figure 1A). Gut barrier function was assessed by transepithelial electrical resistance (TEER) and passage of 457Da Lucifer Yellow from the mucosal to the serosal side using Ussing chambers. mRNA and protein expression of tight junction protein (Cldn2, Cldn4, Ocln) was evaluated in proximal and distal colon. Inflammation was assessed by colonic mRNA levels of Il6, Ccl2 and Tnf and colon weight/length ratio. Fibrotic markers (Acta2, Col1a1, Col3a1, Ccn2, Tgfb1) were assessed in proximal and distal colon by RT-qPCR and western blot. Statistical analysis was performed between SMA MORE and WT mice using Mann-Whitney test. Results MR overexpression in SMCs decreased TEER in male mice (p < 0.01), whereas it increased Lucifer Yellow levels in both sexes (p < 0.05) (Figure 1B). No statistical differences were found in colonic mRNA and protein levels of Cldn2, Cldn4, and Ocln, between SMA MROE and WT mice in both sexes. While overexpression of MR in SMCs did not impact inflammatory markers, it tended to increase mRNA levels of Acta2 (p = 0.0540), Col3a1 (p = 0.0541) and Ccn2 (p = 0.0541) in male mice at distal colon. Conclusion Overexpression of MR in SMCs induced colonic hyperpermeability, which seems to be explained by the altered expression levels of tight junction proteins. MR overexpression in SMCs did not induce the expression of fibrotic markers or inflammatory markers in basal conditions. Further studies are needed to elucidate the involvement of SMC-expressed MR in tissue repair in pathophysiological conditions. Reference: 1. Amamou, A., Leboutte, M., Breton, J. et al. Mineralocorticoid receptor activation contributes to intestinal fibrosis through neutrophil gelatinase-associated lipocalin in preclinical models. Nat Commun 16, 6318 (2025). Conflict of interest: Dr. Leboutte, Mathilde: No conflict of interest Chatel, Emma: No conflict of interest Bôle-Feysot, Christine: No conflict of interest Jaisser, Frederic: No conflict of interest Savoye, Guillaume: No conflict of interest Marion-Letellier, Rachel: No conflict of interest

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