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.
