σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury

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.

The role of Sigma-1 receptor in sex-specific heat shock response in an experimental rat model of renal ischaemia/reperfusion injury

“…Recently, we confirmed the presence of S1R in proximal tubular cells and showed the receptor's translocation upon ligand stimulation . Here we demonstrated that E2 acts directly on S1R and induces the production of heat shock proteins in proximal tubular cells.…”

“…All reagents for Western blot were purchased from Bio‐Rad Laboratories (Hercules, CA, USA). Total protein was extracted from kidney cortex and HK‐2 cells as described previously . Protein concentrations were determined in triplicates by Bradford analysis using bovine serum albumin as standard.…”

“…Sigma‐1 receptor (S1R) is a highly conserved chaperone protein which has mainly been studied in the central nervous system, but is also expressed in peripheral tissues . We showed that activation of S1R induces the Akt–NOS pathway leading to improved renal perfusion after I/R injury . While the beneficial effects of S1R activation have already been implicated in ischaemic brain and cardiac damage , we were the first to describe this protective phenomenon in the kidney.…”

May a sigma‐1 antagonist improve neuropathic signs induced by cisplatin and vincristine in rats?

“…There are few studies showing the vascular effects of the σ1R modulation (Hosszu et al., ; Tagashira et al., ), although some recent studies showed σ1R expression in vascular tissue (Amer et al., ; Bhuiyan, Tagashira, Shioda, & Fukunaga, ). The repeated administration of MR‐309 was able to correct both the increase in coronary perfusion pressure and endothelial dysfunction in the aorta, which agree with our previous recordings in diabetic rats, demonstrating that MR‐309 treatment can improve vascular parameters (Paniagua et al., ).…”

Systolic blood pressure as a potential target of sigma‐1 receptor agonist therapy

“…1,2 Several studies demonstrate that sigma-1 receptor stimulation promotes neuroprotection, neuroplasticity, cardioprotection, and renoprotection. [3][4][5] Accordingly, the sigma-1 receptor is a major target of ongoing pharmaceutical research.…”