title: Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia.
abstract: AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628.
authors.affiliation: INSERM, UMRS 1138, Team 1, 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: INSERM, UMRS 1138, Team 1, 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: INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France;
authors.forename: Fouad
authors.initials: F
authors.lastname: Fadel
authors.affiliation: INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France;
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Moghrabi
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.affiliation: Bayer Healthcare, Cardiology Research, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.affiliation: INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000818:Animals; D002867:Chromones / Q000627:therapeutic use; D004095:Dihydropyridines / Q000627:therapeutic use; D007668:Kidney / Q000098:blood supply*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000187:drug effects*; D015427:Reperfusion Injury / Q000188:drug therapy*; D013434:Sulfenic Acids / Q000494:pharmacology*
chemical_list: C000608139:BR-4628; D002867:Chromones; D004095:Dihydropyridines; D000451:Mineralocorticoid Receptor Antagonists; D044023:Receptor, Endothelin B; D013434:Sulfenic Acids
keywords: acute renal failure; aldosterone; ischemia-reperfusion; nitric oxide