Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice

• Main Authors: Qian Ren, Fan Guo, Sibei Tao, Rongshuang Huang, Liang Ma, Ping Fu
• Format: Article
• Language: English
• Published: Elsevier 2020-02-01
• Series: Biomedicine & Pharmacotherapy
• Subjects: Fisetin; Sepsis; Acute kidney injury; Lipopolysaccharide; Inflammation; Apoptosis
• Online Access: http://www.sciencedirect.com/science/article/pii/S0753332219353946

Background: Sepsis is defined as end-organ dysfunction resulting from the host’s inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown. Purpose: The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice. Methods: The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression. Results: Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression. Conclusion: Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways