σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury

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 σ 1-receptor activation in mediating this protection. In rats, pretreatment with either dehydroepiandrosterone or fluvoxamine, a high–affinity σ 1–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 σ 1-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 σ 1-receptor knockdown or Akt inhibition. Similarly, in the postischemic rat kidney, σ 1-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 σ 1-receptor antagonist or various nitric oxide synthase blockers. In conclusion, in this rat model of ischemia-reperfusion injury, σ 1-receptor agonists improved postischemic survival and renal function via activation of Akt–mediated nitric oxide signaling in the kidney. Thus, σ 1-receptor activation might provide a therapeutic option for renoprotective therapy.