Tetrahydrocurcumin Attenuates Polymyxin B Sulfate-Induced HK-2 Cells Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Mediated PERK/eIF2α/ATF4/CHOP Signaling Pathway Axis

The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB-induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB-induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB-induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB-induced nephrotoxicity in an in vitro model of PMB-induced cell injury. Moreover, we demonstrated that THC effectively protected HK-2 cells from PMB-induced apoptosis by using cell counting kit-8 and flow cytometry assay. THC could also suppress PMB-induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB-induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB-induced nephrotoxicity by inhibiting the ER stress-mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB-induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment.