σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury

J Am Soc Nephrol. 2017 Jan;28(1):152-165. doi: 10.1681/ASN.2015070772. Epub 2016 Apr 7.

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.

Keywords: Sigma-1 receptor; ischemia-reperfusion; kidney; nitric oxide.

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Dehydroepiandrosterone / therapeutic use*
  • Fluvoxamine / therapeutic use*
  • Kidney / blood supply*
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, sigma / agonists*
  • Reperfusion Injury / complications
  • Reperfusion Injury / prevention & control*
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Sigma-1 Receptor

Substances

  • Receptors, sigma
  • Serotonin Uptake Inhibitors
  • Dehydroepiandrosterone
  • Fluvoxamine