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The Mineralocorticoid Receptor Antagonist Eplerenone Suppress Interstitial Fibrosis in Subcutaneous Adipose Tissue in Type 2 Diabetes Patients

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posted on 28.10.2020, 15:43 by Ada Admin, Marie Louise Johansen, Jaime Ibarrola, Amaya Fernández-Celis, Morten Schou, Mette Pauli Sonne, Maria Refsgaard Holm, Jon Rasmussen, Flemming Dela, Frederic Jaisser, Jens Faber, Patrick Rossignol, Natalia Lopez-Andres, Caroline Kistorp
Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association between the MR, fibrosis and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present sub-study including 30 participants was prespecified as part of the Mineralocorticoid Receptor Antagonist in type 2 Diabetes (MIRAD) trial, randomizing patients to either high dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examinations and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen type I and VI, and the profibrotic factor α-smooth muscle actin, as compared to placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusions, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

Funding

A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond for the promotion of medicine, Danish Diabetes Academy, Foundation de France 00086498, Herlev Hospital Research Foundation, Instituto de Salud Carolos III-FEDER”, Fondo de Investigaciones Sanitarias PI18/01875, Miguel Servet contract CP13/00221, The Danish Heart Foundation 15-R99-A5855, The Danish Medical Association Research Foundation

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