title: Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1.
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 of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 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 Large White 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-mediated MR 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.
authors.affiliation: 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.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Barrera-Chimal
authors.affiliation: 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.
authors.forename: Gwennan
authors.initials: G
authors.lastname: André-Grégoire
authors.affiliation: 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.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: 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.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Lechner
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cau
authors.affiliation: 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.
authors.forename: Sonia
authors.initials: S
authors.lastname: Prince
authors.affiliation: Cardiology Research, BAYER Pharma AG, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.affiliation: 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.
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sauzeau
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Hauet
authors.affiliation: 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; frederic.jaisser@inserm.fr.|Clinical Investigation Centre 1433, Institut National de la Santé et de la Recherche Médicale, Vandoeuvre-lès-Nancy, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle; D009479:Neuropeptides / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications; D013552:Swine; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: aldosterone; ischemia-reperfusion; oxidative stress; vascular