Forsythiaside A Ameliorates Sepsis-induced Acute Kidney Injury via Anti-inflammation and Antiapoptotic Effects by Regulating Endoplasmic Reticulum Stress

Abstract

Abstract Ethnopharmacological relevance Sepsis is a systemic inflammatory response syndrome caused by infection in the body, and accompanying acute kidney injury (AKI) is a common complication of sepsis and is associated with increased mortality and morbidity. Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine. Aims of the study: This study aimed to elucidate the protective effect of Forsythiaside A (FTA) on sepsis-induced AKI by downregulating inflammatory and apoptotic responses, and to further explore its underlying mechanism. Methods: Septic AKI was induced by intraperitoneal injection of LPS (10 mg/kg) using male C57BL/6 mice and pretreated with FTA or control saline. First, we assessed the degree of renal injury by creatinine, blood urea nitrogen measurement, and HE staining of renal tissue; secondly, the inflammation and apoptosis were measured by TUNEL immunofluorescence, qPCR, and ELISA; finally, the mechanism was explored by computer molecular docking and Western blot. Results: Our data showed that FTA markedly attenuated kidney pathological injuries, alleviated the elevation of serum BUN and Creatinine, suggesting the renal protective effect of FTA. Notably, FTA significantly inhibited the renal expression of proinflammatory cytokine IL-1β, IL-6, and TNF-α both at protein and mRNA levels and attenuated cell apoptosis in kidney, as measured by caspase-3 immunoblot and TUNEL assay, indicating its anti-Inflammation and antiapoptotic properties. Mechanistically, administration of LPS resulted in robust endoplasmic reticulum (ER) stress responses in kidney, evidenced by glucose-regulated protein 78(GRP78) upregulation, protein kinase RNA–like endoplasmic reticulum kinase (PERK) activation, eukaryotic initiation factor 2 alpha (elF2α) phosphorylation and C/EBP homologous protein (CHOP) overexpression, which could be significant blocked by FTA pretreatment. Dynamic simulation and molecular docking were performed to provide further insight. Conclusions: Collectively, our data suggest that FTA ameliorates sepsis-induced acute kidney injury via its anti-Inflammation and antiapoptotic properties by regulating PERK signaling dependent ER stress responses.