The α7 nicotinic acetylcholine receptor agonist PNU-282987 ameliorates sepsis-induced acute kidney injury through CD4+CD25+ regulatory T cells in rats

The ameliorative effects of alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) agonists have been demonstrated in acute kidney injury (AKI) caused by multiple stimulations. However, the ameliorative effect of alpha 7nAChR on sepsis-induced AKI (SAKI) in the cecal ligation and puncture (CLP) model is unclear. The previous studies have demonstrated that alpha 7nAChR is highly expressed on the surface of CD4+CD25+ regulatory T cells (Tregs). However, the role of Tregs in SAKI is unclear. We hypothesized that Tregs might play a role in the ameliorative effect of alpha 7nAChR on SAKI. Hence, in this study, we determined the effects of PNU-282987 (a selective alpha 7nAChR agonist) on SAKI and evaluated whether PNU-282987 would attenuate SAKI through regulating Tregs. Our study showed that immediate administration of PNU-282987 after CLP surgery in rats improved renal function, reduced levels of systemic inflammatory factors (tumor necrosis factor-alpha, interleukin-6, etc.), inflammatory cell infiltration and tubular apoptosis in renal tissues, and increased forkhead/winged helix transcription factor p3 (Foxp3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression indicating activated Tregs. Moreover, in in vitro experiments, isolated Tregs cocultured with PNU-282987 also displayed enhanced expression of CTLA-4 and Foxp3. Furthermore, Tregs were cocultured with PNU-282987 for 24 hours and then reinfused into rats through the tail vein immediately after CLP surgery, and a significant renal protective effect was observed 24 hours postoperatively. These results demonstrate that PNU-282987 exerts its renal protective effects on SAKI through activation of Tregs.

Automated summary

This study reveals the beneficial effects of the alpha 7 nicotinic acetylcholine receptor agonist PNU-282987 on sepsis-induced acute kidney injury. The findings suggest that the activation of regulatory T cells (Tregs) may contribute to the renal protective effects of PNU-282987.