Kivonat:
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 ofsigma1-receptor activation in mediating this protection. In rats, pretreatment with either dehydroepiandrosterone or fluvoxamine, a high-affinitysigma1-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 thesigma1-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 bysigma1-receptor knockdown or Akt inhibition. Similarly, in the postischemic rat kidney,sigma1-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 thesigma1-receptor antagonist or various nitric oxide synthase blockers. In conclusion, in this rat model of ischemia-reperfusion injury,sigma1-receptor agonists improved postischemic survival and renal functionviaactivation of Akt-mediated nitric oxide signaling in the kidney. Thus,sigma1-receptor activation might provide a therapeutic option for renoprotective therapy.
