σ1-receptor agonism protects against renal ischemia-reperfusion injury

Adam Hosszu, Zsuzsanna Antal, Lilla Lenart, Judit Hodrea, Sandor Koszegi, Dora B. Balogh, Nora F. Banki, L. Wágner, Adam Denes, P. Hamar, Peter Degrell, A. Vannay, Attila J. Szabo, Andrea Fekete

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)152-165
Number of pages14
JournalJournal of the American Society of Nephrology
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

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Reperfusion Injury
Fluvoxamine
Kidney
Nitric Oxide
Dehydroepiandrosterone
Nitric Oxide Synthase
Nitric Oxide Synthase Type I
Survival
Nitric Oxide Synthase Type III
Photons
Vasodilation
Endoplasmic Reticulum
Cytosol
Protein Isoforms
Oxidative Stress
Therapeutics
Epithelial Cells

ASJC Scopus subject areas

  • Nephrology

Cite this

Hosszu, A., Antal, Z., Lenart, L., Hodrea, J., Koszegi, S., Balogh, D. B., ... Fekete, A. (2017). σ1-receptor agonism protects against renal ischemia-reperfusion injury. Journal of the American Society of Nephrology, 28(1), 152-165. https://doi.org/10.1681/ASN.2015070772

σ1-receptor agonism protects against renal ischemia-reperfusion injury. / Hosszu, Adam; Antal, Zsuzsanna; Lenart, Lilla; Hodrea, Judit; Koszegi, Sandor; Balogh, Dora B.; Banki, Nora F.; Wágner, L.; Denes, Adam; Hamar, P.; Degrell, Peter; Vannay, A.; Szabo, Attila J.; Fekete, Andrea.

In: Journal of the American Society of Nephrology, Vol. 28, No. 1, 01.01.2017, p. 152-165.

Research output: Contribution to journalArticle

Hosszu, A, Antal, Z, Lenart, L, Hodrea, J, Koszegi, S, Balogh, DB, Banki, NF, Wágner, L, Denes, A, Hamar, P, Degrell, P, Vannay, A, Szabo, AJ & Fekete, A 2017, 'σ1-receptor agonism protects against renal ischemia-reperfusion injury', Journal of the American Society of Nephrology, vol. 28, no. 1, pp. 152-165. https://doi.org/10.1681/ASN.2015070772
Hosszu, Adam ; Antal, Zsuzsanna ; Lenart, Lilla ; Hodrea, Judit ; Koszegi, Sandor ; Balogh, Dora B. ; Banki, Nora F. ; Wágner, L. ; Denes, Adam ; Hamar, P. ; Degrell, Peter ; Vannay, A. ; Szabo, Attila J. ; Fekete, Andrea. / σ1-receptor agonism protects against renal ischemia-reperfusion injury. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 1. pp. 152-165.
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