AccueilAccueil>Publication dans JASN pour Jonatan Barrera-Chimal, équipe de Frédéric JAISSER

Publication dans JASN pour Jonatan Barrera-Chimal, équipe de Frédéric JAISSER

Benefit of Mineralocorticoid Receptor Antagonism in
AKI: Role of Vascular Smooth Muscle Rac1


Jonatan Barrera-Chimal*, Sonia Prince*, Fouad Fadel*, Soumaya El Moghrabi*, David G. Warnock†, Peter Kolkhof‡ and Frédéric Jaisser*

*Jonatan Barrera-Chimal,* Gwennan André-Grégoire,* Aurelie Nguyen dinh Cat,*Sebastian M. Lechner,* Jérôme Cau,†‡ Sonia Prince,* Peter Kolkhof,§ Gervaise Loirand,|
Vincent Sauzeau,| Thierry Hauet,†‡ and Frédéric Jaisser*

*Unité Mixte de Recherche Scientifique 1138, Team 1, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France; †Unité U1082 Ischemie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques, Institut National de la Santé et de la Recherche Médicale, Université de Poitiers, Poitiers, France; ‡Service de Biochimie, Centre Hospitalier Universitaire de Poitiers, Pôle BIOlogie Santé publique PHARMacie, Poitiers, France; §Cardiology Research, BAYER Pharma AG, Wuppertal, Germany; |Unité Mixte de Recherche Scientifique 1087, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Unité Mixte de Recherche Scientifique 6291, l’Institut du Thorax, Nantes, France; and ¶Clinical Investigation Centre 1433, Institut National de la Santé et de la Recherche Médicale, Vandoeuvre-lès-Nancy, France

Correspondence:
Dr. Frédéric Jaisser, U1138, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Team 1, 15 rue de l’Ecole de Médecine, 75006 Paris,
France. Email: frederic.jaisser@inserm.fr

Abstract

AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect ofMR antagonismin IR-induced AKI in the Large White pig, amodel of human AKI. Inmice, MR deficiency in smoothmuscle cells (SMCs) protected against kidney IR injury.MR blockade by the novel nonsteroidalMR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, requiredforNADPHoxidase activation, than shamcontrol kidneys, andgeneticdeletionofRac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the LargeWhite pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediatedMR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.

 


 

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