Hydrogen Sulfide Alleviated Polystyrene Nanoplastic-Induced Kidney Injury by Inhibiting ROS-Triggered Endoplasmic Reticulum Stress

Background: Polystyrene nanoplastics (PS-NPs) are emerging contaminants that may pose a risk to human kidney health. This study investigated whether endoplasmic reticulum stress (ERS) contributes to PS-NP-induced kidney injury and explored the potential role of hydrogen sulfide (H2S) in the underlying mechanism. Methods: Kidney dysfunction, fibrosis, ERS, oxidative stress, Cu/Zn superoxide dismutase (SOD) activity, cystathionine-γ-lyase (CSE) expression, and plasma H2S levels were assessed following 4 weeks of PS-NPs exposure. The effects of the ATF6 inhibitor melatonin and exogenous H2S supplementation were also evaluated. Using a Biacore SPR system, experiments were performed to investigate the interaction between PS-NPs and Cu/Zn SOD and to determine whether H2S affects this interaction. Results: PS-NPs exposure induced kidney dysfunction and fibrosis and increased the expression of activating transcription factor 6 (ATF6) and glucose-regulated protein 78 (GRP78) levels. Treatment with melatonin alleviated PS-NPs-induced kidney dysfunction and fibrosis. PS-NPs also aggravated renal oxidative stress by inhibiting Cu/Zn SOD activity, while reducing renal CSE expression and plasma H2S levels. Exogenous H2S supplementation attenuated renal oxidative stress, reduced ERS, and subsequently ameliorated kidney dysfunction and fibrosis. In vitro, PS-NPs directly bound to Cu/Zn SOD and decreased its enzymatic activity. H2S restored Cu/Zn SOD activity by interfering with the interaction between PS-NPs and Cu/Zn SOD. Conclusions: H2S alleviates PS-NP-induced kidney dysfunction and fibrosis by restoring Cu/Zn SOD activity, thereby reducing the activation of the ATF6-GRP78 pathway. These findings identify the H2S/Cu/Zn SOD axis as a potential mechanism underlying PS-NP-induced kidney injury and as a possible therapeutic target.