title: σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury.
abstract: Mechanisms of renal ischemia-reperfusion injury remain unresolved, and effective therapies are lacking. We previously showed that dehydroepiandrosterone protects against renal ischemia-reperfusion injury in male rats. Here, we investigated the potential role of σ1-receptor activation in mediating this protection. In rats, pretreatment with either dehydroepiandrosterone or fluvoxamine, a high-affinity σ1-receptor agonist, improved survival, renal function and structure, and the inflammatory response after sublethal renal ischemia-reperfusion injury. In human proximal tubular epithelial cells, stimulation by fluvoxamine or oxidative stress caused the σ1-receptor to translocate from the endoplasmic reticulum to the cytosol and nucleus. Fluvoxamine stimulation in these cells also activated nitric oxide production that was blocked by σ1-receptor knockdown or Akt inhibition. Similarly, in the postischemic rat kidney, σ1-receptor activation by fluvoxamine triggered the Akt-nitric oxide synthase signaling pathway, resulting in time- and isoform-specific endothelial and neuronal nitric oxide synthase activation and nitric oxide production. Concurrently, intravital two-photon imaging revealed prompt peritubular vasodilation after fluvoxamine treatment, which was blocked by the σ1-receptor antagonist or various nitric oxide synthase blockers. In conclusion, in this rat model of ischemia-reperfusion injury, σ1-receptor agonists improved postischemic survival and renal function via activation of Akt-mediated nitric oxide signaling in the kidney. Thus, σ1-receptor activation might provide a therapeutic option for renoprotective therapy.
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and.|First Department of Pediatrics.
authors.forename: Adam
authors.initials: A
authors.lastname: Hosszu
authors.affiliation: First Department of Pediatrics.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Antal
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and.
authors.forename: Lilla
authors.initials: L
authors.lastname: Lenart
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and.
authors.forename: Judit
authors.initials: J
authors.lastname: Hodrea
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and.
authors.forename: Sandor
authors.initials: S
authors.lastname: Koszegi
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and.
authors.forename: Dora B
authors.initials: DB
authors.lastname: Balogh
authors.affiliation: First Department of Pediatrics.
authors.forename: Nora F
authors.initials: NF
authors.lastname: Banki
authors.affiliation: Department of Transplantation and Surgery, and.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Denes
authors.affiliation: Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Hamar
authors.affiliation: Department of Pathology, Moritz Kaposi General Hospital, Kaposvar, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Degrell
authors.affiliation: MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Vannay
authors.affiliation: First Department of Pediatrics.|MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Szabo
authors.affiliation: MTA-SE Lendulet Diabetes Research Group and fekete.andrea@med.semmelweis-univ.hu.|First Department of Pediatrics.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fekete
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D003687:Dehydroepiandrosterone / Q000627:therapeutic use*; D016666:Fluvoxamine / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists*; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D000097605:Sigma-1 Receptor
chemical_list: D003687:Dehydroepiandrosterone; D016666:Fluvoxamine; D017480:Receptors, sigma; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor
keywords: Sigma-1 receptor; ischemia-reperfusion; kidney; nitric oxide