Sigma1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury

Hosszú, Ádám and Antal, Zsuzsanna and Lénárt, Lilla and Hodrea, Judit and Kőszegi, Sándor and Balogh, Dóra Bianka and Bánki, Nóra Fanni and Wágner, László József and Dénes, Ádám and Hamar, Péter and Degrell, Péter and Vannay, Ádám and Szabó, Attila and Fekete, Andrea (2017) Sigma1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 28 (1). pp. 152-165. ISSN 1046-6673

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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 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.

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